Safer Medicines - putting patient safety first

Putting patient safety first

Quotes from Doctors & Researchers:

It is often claimed that scientists and doctors are united in their belief in the value of, and necessity for, animal experiments to protect human health. This stream of quotes from scientists and doctors, stretching from as far back as the early 20th Century right up to today, shows that there has been a long tradition of scepticism about this issue. Many of the quotes are from scientists who support or conduct animal research; far from diminishing the impact of their words, this fact ought to give them extra weight.

Note: FDA stands for Food and Drug Administration, the US drug regulatory body.

Cancer | Neurological diseases/ conditions | Teratogenicity and thalidomide | Immunology & AIDS & TGN1412 | Miscellaneous

Miscellaneous

2014

Much of the high failure rate associated with the use of nonhuman animal models to predict human reactions to new drugs is due to fundamental differences in biology between species. "These differences often result in inefficient and costly experiments that do not provide accurate answers about the toxicity of a drug in humans. It takes about $5 billion on average to develop a drug, and 60 percent of that figure comes from upfront costs in the research and development phase. Using a well-designed model of a human organ could significantly cut the cost and time of bringing a new drug to market."

Kevin Healy, Professor of Bioengineering, University of California, Berkeley

phys.org/news/2015-03-bioengineers-human-hearts-chip-aid.html

"We’re extracting some cartoon version of the disease, and then treating it, so that the animal model becomes the focus of our research, not that actual human disease. And we learn more and more about the model, but not the disease."

Susan M. Fitzpatrick, Adjunct Associate Professor, Neurobiology, Washington University.

chronicle.com/article/A-Modern-Clinical-Trial-7/151355/

"We are replacing animal testing right now… These systems ["human on a chip"] allow a much greater understanding of the mechanisms of the human body and give us insights that are not possible with animal studies."

Geraldine Hamilton, senior staff scientist at Harvard university's Wyss Institute

http://www.ibtimes.co.uk/artificial-human-farms-could-wipe-out-animal-testing-three-years-scientists-claim-1463357

2013

"The problem is that mice are never really man and they deal with the biology in life very differently than we do. For example, mice don’t get most of the neurological diseases that we are very interested in studying, like Alzheimer’s, Parkinson’s and schizophrenia – these things were bred out of mice sixty million years ago when the split between mice and primates occurred. So this is the real challenge, is that if you really want to understand human biology, you need to really be working in human material and we failed to do that for a very long time."

Dr Sandra Engle, Senior Principal Scientist, Pfizer Global Research and Development

Mice are Never Men- Stem Cell Derived Cells as Models - Pharma IQ

“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.” 

Dr Elias Zerhouni, Director of the US National Institutes of Health (NIH: the world's largest supporter of medical research) from 2002-2008.

http://nihrecord.od.nih.gov/newsletters/2013/06_21_2013/story1.htm

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

Dr Ronald W. Davis, genomics expert, Stanford University

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

Dr. Richard Hotchkiss, sepsis researcher, Washington University

Gina Kolata, New York Times, February 11 2013

"The current paradigm does not work. The drug discovery process is stagnating. Now is the time to reverse that. We have the solutions, we've got the technologies, now we need to work together to implement them. What we have here is an opportunity to replace a broken system that is only going to get worse, with a system that is not only cheaper, not only more ethical, not only more efficacious, not only safer, but also more scientifically valid. It will require investment and perhaps legislative encouragement but this short-term investment will reap huge long-term gains. If we don't act now, revisit the requirement for animal testing, and address the application of these alternative models, we risk losing both the testing and the development of the alternative technologies to emerging market economies - companies like GSK are already starting to move their testing into China, Brazil and India."
Dr Meg Lewis of Kirkstall Ltd, The animal-free future of drug discovery' at CASJ 'Animal Research, Ethics and Public Policy' Seminar, 4 July 2013 at University of Leicester
http://www.youtube.com/watch?v=h5bKPa-wp7Q

2012

“Animal models often fail to predict results in human clinical trials, and this has had a devastating effect on drug development. Not only have costs skyrocketed, but fewer and fewer good drugs are in the pipeline, and so fewer good drugs are reaching patients.” 

Professor Don Ingber, founding director of the Wyss Institute and Professor at Harvard Medical School and Boston Children’s Hospital. 

www.asbmb.org

“Clearly, current animal models seem to be incapable of predicting results in human trials of new agents."

Dr Mitchell Fink, surgeon and sepsis expert, University of California, Los Angeles.  

Raven, K: Rodent models of sepsis found shockingly lacking. Nature Medicine 2012, 18:998-998

“R&D in pharma has been isolating itself for 20 years, thinking that animal models would be enough and highly predictive, and I think I want to just bring back the discipline of outstanding translational science, which means understand the disease in humans before I even touch a patient.” 

Elias Zerhouni, former director of NIH and current head of R&D at Sanofi. 

Forbes Magazine, June 25, 2012

“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.

Our proposed solution is to do studies with human cells – but not just cells in a dish—cells that exhibit organ-like structures and functions. We’re working on more than 10 different organs right now. The goal is to link them together with little fluidic channels, like blood vessels, like they are in our bodies."

Dr Don Ingber, director of Harvard University's Wyss Institute of Biologically Inspired Engineering. Technology Review, July/August 2012 www.technologyreview.com/demo/427992/building-an-organ-on-a-chip/

"A thousand years ago Ibn Sina warned against incautious extrapolation from animal experiments to humans; yet, as the study by Petticrew and Davey Smith illustrates, this practice continues today”. Sir Iain Chalmers, co-founder of the Cochrane Collaboration and coordinator of the James Lind Initiative. www.sciencedaily.com/releases/2012/03/120321172219.htm

2011

Virtually all advances in the control of human disease begin with observations at the bedside. No amount of basic research will lead to improvements in patient care. The effective paradigm for advancing control of HUMAN disease is “Bedside to Bench, and Back”. 

Emil J Freireich, MD. 

http://blogs.wsj.com/health/2011/04/15/former-merck-head-vagelos-says-nih-should-stick-to-basic-research/

“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.” 

FDA Commissioner Margaret Hamburg.

Advancing Regulatory Science. Science 2011, 331:987

"With earlier and more rigorous target validation in human tissues, it may be justifiable to skip the animal model assessment of efficacy altogether."

Dr Francis Collins, Director of the US National Institutes of Health.

http://stm.sciencemag.org/content/3/90/90cm17.full

"Mice are mice, and people are people. If we look to the mouse to model every aspect of the disease for man, and to model cures, we're just wasting our time.... [The mouse] has cost us a new generation of medicines... The vast majority of the money that we spend in clinical trials based on mouse data is completely wasted... We keep getting led down the garden path. We've had thousands of mouse studies of tuberculosis, yet not one of them has ever been used to pick a new drug regimen that succeeded in clinical trials. This isn't just true for TB; it's true for virtually every disease. We're spending more and more money and we're not getting more and more drug candidates." Clif Barry, Chief of the Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
www.slate.com/articles/...human_disease_.html

An over-reliance on animal models at an early stage is now thought to be the biggest cause of failure at phases II and III [clinical trials]. Using animal models is not producing efficacious human medicines. Human tissue research presents the most exciting and advanced approaches that medical science currently has to offer. It is time for the use of human tissue to become the gold standard for the pharmaceutical industry.
World Pharmaceutical Frontiers 2011, Vol 1, p132 http://www.scribd.com/doc/58341153/World-Pharma-2011-Vol-1

Testing the toxicity of pharmaceutical candidates in lab animals to support the safety for human clinical trials is notoriously unreliable. Often compounds that appear safe in rodents prove to be toxic in humans.
Dr Aaron Heifetz, Drug Discovery World, Fall 2011, p102011

“We spend billions of dollars on biomedical research in animals that too often doesn’t give us much real information about how a chemical or device will behave in people,” Professor Hartung said. Testing one new substance in rats costs roughly $1 million and takes about 4 years to get results. “This is not anything we want to see in the production cycle. Producers and regulators alike want something faster and cheaper and this is not going to come from continued animal testing,” Hartung said.
http://www.naplesnews.com/news/2011/may/08/animal-testing-advocates-cruelty-research-humane/

"Mice predict the effect on humans with about 43 percent efficiency, so sometimes it would seem that tossing a coin would give a better result'' - Dr. Thomas Hartung, Director of the Center for Alternatives to Animal Testing at Johns Hopkins University in Baltimore.
He cites the search for new drugs to treat sepsis, or bloodstream infections. In recent decades, 43 substances have gone to clinical trials in humans after showing promise in animals.

"Of all those drugs, one showed slight improvement for patients, two made them worse and the rest, no effect," he said. "You could save millions if we were rats, but we are not 150-pound rats. But by the same token, no one knows how many valuable treatments have never made it to clinical trials because some rats had a problem with them that humans may not have experienced."
http://www.gosanangelo.com/news/2011/may/14/search-on-for-alternatives/

2010

Participants in clinical trials may be put at unnecessary risk if efficacy in animals has been overstated – Professor Malcolm Macleod and colleagues, Centre for Clinical Brain Sciences, University of Edinburgh, PLoS Biol 2010 8(3): e1000344

Failure to recognize that many standard control rats and mice used in biomedical research are sedentary, obese, glucose intolerant, and on a trajectory to premature death may confound data interpretation and outcomes of human studies – Bronwen Martin and colleagues, National Institute on Aging, Maryland, PNAS 2010 107(14): 6127

We want to migrate away from animal testing. We also want to see drug development become more efficient so that fewer resources are wasted – David Jacobson-Kram, executive director for pharmacology and toxicology, FDA, Bloomberg News, 5 August 2010

2009

It started out not wanting to hurt bunnies, but we've found that using [human equivalent] tissue is better science, more cost effective, and much more accurate than doing the same tests on animals. Dave Ingalls, spokesman for MatTek. Quoted by Colin Nickerson, the Boston Globe, 30th March.

Over the last twenty years e-learning has transformed the way in which university students are taught and supported in their learning. For many students it is even possible to replace laboratory-based practical classes in disciplines such as pharmacology and physiology by computer-based learning programs which have been shown to offer effective alternatives to traditional teaching methods - similar learning objectives are achieved, costs are often lower, students are happy and unnecessary use of animals is reduced. David Dewhurst, Professor of E-Learning at Edinburgh University http://www.politics.co.uk/opinion-formers/press-releases/animal-welfare/adi-meps-buckle-under-vivisection-industry-pressure-$1293593$464772.htm

The following quotes are all from Dr Kelly BéruBé, Cardiff University, speaking on the Today Programme, BBC Radio 4, 4th June

Now we can do our experiments in petri dishes with functional human tissue. Now you have human data, so no need for the rat. I say, why use a rat when a human lung will do?

I don’t see any reason why we can’t use human tissue. It’s the best way to go. You get human end point data, you don’t have to worry about saying, well, this happened in the rat, this might happen in man. So you can do it. It’s just a matter of having an application, a tissue supply & of course funding from agencies such as the NC3Rs.

There are people using neuronal tissue in tissue engineering,

They (in silico modellers) are basically taking data from animal experiments & seeing if they can run them on computer models & get the same results. So I’d like them (in silico modellers) to start working on modelling the results that we get from our tissue models & then see if they marry up. I think that will bring us more advance than using rodents. I’m talking about lung biology here & they use the rats traditionally & the data never matches up.

2008

Heidi Ledford in Nature 2008 (453 (7197):843-5):
In April this year, Nobel laureate Sydney Brenner brought the crowd to its feet at the American Association for Cancer Research meeting in San Diego, California. Brenner pioneered the use of the nematode Caenorhabditis elegans as a simple model for studying growth and development. But in his talk, he championed experiments on a more complicated creature: Homo sapiens. “We don't have to look for model organisms anymore because we are the model organism,” he said.

Drug disasters are literally built into the current system of drug testing and approvals in the United States – Donald Light, Professor of comparative health policy at the University of Medicine and Dentistry of New Jersey, American Sociological Association press release, 3rd August 2008

Mice are lousy models for clinical studies... We can’t depend on the mouse for all the answers, because in some cases it’s not giving us the right answers. But think about what we can do with people. People come to hospitals, get vaccinations, give blood and tissue samples for routine lab tests and clinical trials. We’re not learning nearly as much as we could from these samples. We seem to be in a state of denial, where there is so much invested in the mouse model that it seems almost unthinkable to look elsewhere.
– Professor Mark Davis, Director of the Stanford Institute for Immunity, Transplantation and Infection, California.
Immunity 29: 835, 19th December 2008.

Currently, it is a trial and error process to try and predict clinical response, but given the high failure rate [of investigational drugs], clearly it doesn’t work very well.
James Karis, CEO of Entelos
Pharmalot.com, 12th December 2008.

The acid test is what happens in the human. Professor Ian Chopra, a biofilm specialist from Leeds University http://news.bbc.co.uk/go/em/fr/-/1/hi/health/7599818.stm

It's slow. It's expensive. We are not rats and we are not even other primates … After all, ultimately what you are looking for is, does this compound do damage to cells? Can we, instead of looking at a whole animal, look at cells from different organs?
Dr. Francis Collins, Director, National Human Genome Research Institute, speaking to reporters at an American Association for the Advancement of Science conference.

Traditional animal testing is expensive, time-consuming, uses a lot of animals and from a scientific perspective the results do not necessarily translate to humans. It’s a bold, ambitious thing to try to do but our goal is to eliminate animal use in toxicology in ten years. Dr Christopher Austin, Director, National Institutes of Health Chemical Genomics Center, speaking to reporters at an American Association for the Advancement of Science conference.

(Supporters of animal research are) also too unwilling to admit the inadequacies of some aspects of animal research - the benefits are simplistically exaggerated in many cases. Prof Colin Blakemore, quoted by Zoe Corbyn, Times Higher Education, 28 February.

The reason we use animal tests is because we have a comfort level with the process . . . not because it is the correct process, not because it gives us any real new information we need to make decisions. Animal tests are no longer the gold standard, it is a marvelously new world. Melvin E. Andersen, director of the division of computational systems biology at the Hamner Institutes for Health Sciences, USA. Quoted by Gaul, Washington Post, Saturday, April 12, 2008; Page A01

Some animal tests haven't changed in 60 years. The tests are frozen in time. This is not science. Science is always moving ahead. Thomas Hartung, head of the European Centre for the Validation of Alternative Methods. Quoted by Gaul, Washington Post, Saturday, April 12, 2008; Page A01

With more than 250 rat strains and 330 mouse strains to choose from, it is not surprising that the health authorities have been confused for the past 25 years and unbelievably slow to recognise the dangers to human health of BPA (bisphenol A, a component of many plastic products). That is why we used human cells in our analysis. Dr Claude Reiss, president of Antidote Europe (http://www.antidote-europe.org/)

The modern tools of molecular biology now permit the human to be the best model organism to study biology. Dr Arnold J. Levine, Simons Center for Systems Biology, Institute for Advanced Study, Princeton, USA. Journal of Virology, 1st October.

One of the greatest disappointments for the pharmaceutical industry is having experimental compounds that show early promise in animals that later fail miserably when tested in humans. In building our initial model of a 'virtual mouse', scientific teams at Entelos discovered subtle but important differences between species that can have a big impact on interpreting results of animal studies and on designing clinical trials. Our models and predictive platforms help to better translate results and design experiments to make animal studies more meaningful and relevant for finding effective medicines for patients. We plan to increase access to Entelos' powerful simulation technology to enhance researchers' capabilities to rapidly test 'virtual mice' and 'virtual patients' and ultimately use fewer animals, run more decisive clinical trials, and save time and money. James Karis, president and CEO of Entelos http://www.reuters.com/article/pressRelease/idUS56996+08-Apr-2008+BW20080408


The following quotes are all taken from: Prof. Kenneth R. Chien of Massachusetts General Hospital and Harvard University Medical School, Regenerative medicine and human models of human disease, Nature, Vol. 453, 15th May 2008:

- Clearly, a better understanding of disease mechanisms is required for regenerative medicine to succeed. But most of what is known about the molecular pathways that lead to human diseases has come from studying animal models, particularly genetically engineered mouse models, which do not necessarily mimic human physiology or precisely recapitulate human disease. The cardiovascular systems of mice and humans, for example, diverge with respect to serum lipid profiles, the way that abnormalities in heart rhythm develop and the phenotype that results from certain single-gene disorders.

- These technological advances [using human stem cells] provide the opportunity to set up human models of human disease, which should markedly improve the understanding of human disease mechanisms.

- Progress in stem cell technology is beginning to offer the unprecedented possibility of using humans as model organisms.

- In terms of disease, these systems [using human stem cells] could allow the study, for example, of the complex common genetic variants that are now being uncovered by genomewide association studies of patients with specific forms of heart disease, variants that would be extremely difficult to mimic in mice.

- This convergence of human genetics and human stem-cell models could be especially powerful for studying rare chromosomal disorders, such as Down’s syndrome, that are usually associated with numerous physiological changes across multiple organ systems. The chromosomal translocations, deletions and duplications seen in many of these genetic disorders in which several organs are affected have been difficult, if not impossible, to study in model organisms.

- Perhaps we are about to enter a new age of enlightenment in regenerative medicine, with human models of human disease leading the transition from bedside to bench.

The following quotes are all taken from: Heidi Ledford, Nature 452, 510-511 (1st April 2008) (On the use of antiarrhythmic drugs to prevent heart attacks (which actually doubled the risk)):

- Drugs play a prominent part in the management of cardiorespiratory arrest, although rigid clinical evidence to demonstrate their value is sparse. Their use depends principally on tradition, on an unproven expectation that antiarrhythmic effects are likely to be beneficial for potentially lethal arrhythmias as well as for less malignant conditions, and on extrapolation from animal experiments. Chamberlain, Heart, 80: 408-411 (1998).

- It is not easy to think of a greater medical error, since the practice of therapeutic bleeding, than the use of antiarrhythmic drugs in patients after myocardial infarction. Robert Temple, director of the Office of Medical Policy at the US FDA, Clinical Measurement in Drug Evaluation (eds Nimmo, W. S. & Tucker, G. T.) (publ. Wiley) (1995)- cited in the above Nature article.

2007

For quotes from the US National Research Council Report for the US Environmental Protection Agency published this year, see http://curedisease.net/reports/toxicitytesting.shtml .

There is currently no good way of predicting whether a compound is toxic in humans, "Testing in animals is never going to be able to predict all human toxicity. Steven Tannenbaum, professor of toxicology and chemistry at Massachusetts Institute of Technology. Quoted on 29th November in an article by Katherine Bourzac writing in the Technology Review.

We know animal models do not translate to human responses...Animal models of treatments for HIV to psoriasis and flu are not representative of human responses. William Warren, president, CEO and co-founder of VaxDesign, a company that has developed an in vitro human immune system, quoted by Allan Maurer in: VaxDesign developing a clinical trial in a test tube, 2nd October, TechJournal South.

The safest thing to say is that about 70 percent of drug failures occur due to toxicity...There's always a question you have to ask, and that is whether testing on an animal is predictive of how a human will react. Prof Jonathan Dordick, co-founder of Solidus (a company that has helped to develop a new Biochip that uses 3D human tissue cultures to assess the affects of chemicals), quoted by Larry Greenemeier, Scientific American, 21st December 2007.

Today, we can be confident that an approved drug will be effective for its labeled uses. The same cannot be said of the drug’s safety. William B. Schultz, New England Journal of Medicine, 357; 22, 2217-2219.

There is an increased interest & effort from researchers in developing new alternative methods by using human material, since these models will improve the relevance of the results produced. Bremer & colleagues, Alternatives to Laboratory Animals, 35, 421-439.

We believe that experimental findings in animals cannot be extrapolated to
observations in human beings… Leung, Bjarnason and Chan, the Lancet, 369:1691.

According to experts, the liver appears to be the most common target organ for toxicity during the course of drug development, and animal studies appear to be limited at best in predicting human hepatotoxicity. James Karis, CEO of Entelos, quoted in: Entelos to develop liver injury model for the FDA, DrugResearcher.com, 6th August.

In conclusion therefore while some surrogate in vivo models may inform on the mechanisms of human as well as animal disease many others are potentially a menace and may actually slow our progress. Janusz A Jankowski, Professor in GI Oncology & Lea-Anne Harrison, Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary, rapid response to: Comparison of treatment effects between animal experiments and clinical trials: systematic review, British Medical Journal, 334: 197.

It is common (some might say 'fashionable') to conduct studies in KO [Knock Out: where a gene has been turned off] mice, but do such results reveal important aspects of normal physiology and pharmacology or instead, are the findings primarily a description as to how a particular mouse strain compensates (as in the current study) for a total body knockout of a protein essential for caveolae formation and that is absent from embryonic life onward? Given such extensive losses of caveolin-1 and caveolae and the length of time of these losses, are results in these knockout mice physiologically relevant or only pharmacological curiosities? Insel & Patel, British Journal of Pharmacology, 150, 251–254.

Medical science has long been concerned about adverse occurrences in human trials that aren't predicted in traditional animal studies. Gary Dreher, CEO of AMDL. www.drugresearcher.com , 21st May.

Since the natural mouse immune system differs from that in humans, experiments in mice are not always predictive of how therapeutic compounds will work in humans - both in terms of efficacy and side-effects. Gary Dreher, CEO of AMDL. www.drugresearcher.com , 21st May.

It is strange that pharma companies accept to make decisions based on animal data, where the correlation with therapeutic data is highly variable - correlation between PK in rats and PK in humans is between 60 and 70 per cent - but find it difficult to accept data based on human testing. It clearly shows the conservative nature of the industry. Professor Colin Garner, CEO Xceleron Ltd. www.drugresearcher.com, 5th June.

“Professor John Warner, the head of the department of paediatrics at Imperial College, London, said that clinical research should be carried out on children because doctors were currently obliged to scale down treatments designed for adults… he said that about 40 per cent of medicines prescribed to children had never been tested on
them… Professor Warner said that therapies should be designed specifically for children as they have different metabolisms, immature organs and diseases that can behave unexpectedly. He said: ‘We have a desperate need to understand precisely how children’s bodies work so that we can custom-design therapies for them.’” The Times, 9 July.

Unfortunately, novelty does not easily penetrate into the pharmaceutical environment and, in particular, the very conservative world of safety sciences, which all too readily responds with the often heard boring refrain of 'the regulators won't accept these new approaches'! The safety science community should be reminded that regulators expect them to take the initiative to improve their sometimes catastrophic record in predicting clinical drug safety as a result of their investigational efforts. Dr Icilio Cavero, reporting on a Safety Pharmacology Society workshop held at Pfizer, Kent, 13th February 2007. Expert Opinion Drug Safety, 6(4):465-471.


The following quotes are all taken from: Rowell, Journal of Applied Physiology, 102: 837–840.

Understanding of human physiology indeed rests in part on what we have learned from other species, but a great body of knowledge comes from studies performed on human subjects that entailed measurements as accurate and quantitative as those possible in work with animals.

Extrapolation as a means of learning about one species from another has its limits (and dangers)—we would have little luck in understanding the problems for cardiovascular regulation in the giraffe from studies on dogs. No amount of extrapolation would have revealed particular features of human physiology that set this species apart.

Two major disputes concerning Starling's Law of the Heart and active redistribution of blood flow pitted thinking of human physiologists and cardiologists against that of many (not all) animal physiologists. But the findings of both groups were valid: extrapolation of findings from dogs to humans caused major misunderstandings.

It suffices to say here that temperature regulation in humans during heat stress at rest or during exercise is so fundamentally different from that of other species that extrapolation from animals has no meaning.

2006

Animals are very, very poor predictors of human metabolism. These drugs are not being developed for the veterinary market. They're been developed for us. That's why it's (microdosing) hot and promising. Eventually, all first in human tests are going to be in microdoses. Vitalea co-founder & nutritionist, Dr Stephen Dueker, quoted in: Bio-IT World. 15th February.

Relative lack of severe toxicity in animal models should never be construed as a guarantee of safety in man, as the story of thalidomide taught us. Prof Goodyear, British Medical Journal, 332:677-678.

It has been estimated that ~ 50% of the new drugs that produce hepatotoxicity in human clinical studies do not demonstrate any concordance with animal toxicity studies. Caldwell and Yan, Screening for reactive intermediates and toxicity assessment in drug discovery, Current Opinion in Drug Discovery and Development, 9(1):47-60, referring to Olson and colleagues, Concordance of the toxicity of pharmaceuticals in humans and in animals. Regulatory Toxicology and Pharmacology, (2000) 32(1):56-67).

Animal studies suggest that early visual deprivation can cause permanent functional blindness. However, few human data on this issue exist. Given enough time for recovery, can a person gain visual skills after several years of congenital blindness? In India, we recently had an unusual opportunity to work with an individual whose case history sheds light on this question…These results suggest that the human brain retains an impressive capacity for visual learning well into late childhood. They have implications for current conceptions of cortical plasticity and provide an argument for treating congenital blindness even in older children. Ostrovsky and colleagues, Psychological Science, December 2006.

In many cases, we found that, other than having aberrations in insulin-signalling and glucose levels, there was no similarity between the animal model and the human disease condition…If you're developing a drug in that animal model, it's clearly not going to work in humans because they have a different disease. Dr Elliston, CEO, Genstruct. Chemical & Engineering News, Volume 84, Number 31, pp. 17-26.

Conventional animal studies have value, because they are required by law. Professor Johannes Doehmer, CEO GenPharmTox, FRAME lecture, London, November 2006.

Our major finding is that human pancreatic islets have a unique architecture, and work differently than rodent islets. We can no longer rely on studies in mice and rats. It is now imperative that we focus on human islets. At the end of the day, it is the only way to understand how they function. Proceedings of the National Academy of Sciences, 14th February 2006; 103(7): 2334-2339.

Poor replication of even high-quality animal studies should be expected by those who conduct clinical research. Drs Hackam & Redelmeier, Journal of the American Medical Association, October 11, 2006, Vol 296, No. 14 1731-1732.

There's no scientific basis for it. Sometimes it works and sometimes it doesn't. (Commenting on the FDA's historic requirement to test drugs on animals before humans) Dr Carl Peck, director of the University of California, San Francisco's Center for Drug Development Science and former head of the FDA's Center for Drug Evaluation and Research, San Francisco Business Times, 20th January.

Many resources are invested in, and thus wasted on, [animal studies of] candidate products that subsequently are found to have unacceptable profiles when evaluated in humans. US FDA guidance document, Guidance for Industry, Investigators, and Reviewers, Exploratory IND Studies, January.


The following quotes are all taken from: Dr. Bob Coleman, Asterand Plc. Next Gen Pharmaceutical, www.ngpharma.com/pastissue/article.asp?art=268318&issue=170.

- PhaseZEROTM [Asterand's human tissue tests] was established to address what was perceived to be a serious problem for the pharmaceutical industry, namely its staggeringly poor performance in translating good ideas into safe effective medicines. This is no reflection on the quality of the scientists involved, but of the tools available to identify and validate new therapeutic approaches with any certainty. Although the target for such new medicines is man, the methods employed to identify and validate have historically been almost entirely non-human, and their predictivity for man consequently unreliable.

- In many cases however, it may prove that for establishing proof of concept for efficacy, there is no useful animal model. A good example is cystic fibrosis, a disease that in its severest form is invariably fatal... Cystic fibrosis appears to be a uniquely human disorder, and attempts to develop a useful animal model have failed. Indeed, even [cystic fibrosis receptor] knock-out mice fail to display the broncho-pulmonary symptoms that are characteristic of human cystic fibrosis.

- It would be a mistake to consider that only [animal] data have any real relevance in clinical go/no go decisions, and in cases such as cystic fibrosis, where there is little point in utilising animal models, efforts would be better directed towards [Asterand's human tissue tests] studies on human lung epithelial cells in vitro. The results of such studies would provide a much sounder basis for the decision as to whether or not a clinical study is warranted.

- To illustrate, I will use the mouse, for which there has been considerable enthusiasm as a human surrogate, based ostensibly on the much vaunted genetic similarity between the two species. In truth, this enthusiasm is as much a function of the fact that mice are cheap and easy to use, and that there is a vast range of established models available to the experimenter.

- An enthusiasm for established, available animal models in the face of evidence of their unsuitability for purpose is commonplace.

- Early [Asterand's human tissue tests] profiling of troglitazone [a diabetes drug that was withdrawn due to liver toxicity] would have identified a high risk of liver toxicity, and provided a means of identifying a safer compound of comparable efficacy.


This article is timely as it highlights the unsatisfactory surrogate of many animal model systems for human disease…while some surrogate in vivo [animal] models may inform on the mechanisms of human as well as animal disease many others are potentially a menace and may actually slow our progress. Janusz A Jankowski, Professor in GI Oncology & Lea-Anne Harrison, Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary, rapid response to: Comparison of treatment effects between animal experiments and clinical trials: systematic review, British Medical Journal, 334: 197.

"In the animal models, the drug worked beautifully. We had all the evidence of efficacy, the drug was hitting the receptor, but we went into humans and the drug failed miserably. . . Dr Dixit, senior director of toxicology, drug evaluation at Johnson & Johnson Pharmaceutical Research and Development, Drug Discovery and Development, 7th April.

It is undoubtedly the case that all animal models are limited in their predictability for humans. Weatherall, The use of non-human primates in research., Academy of Medical Science.

2005

It has also become clear that available animal models of human disease are often inadequate, necessitating even more research on human populations and biologic samples. Dr Elias Zerhouni, director of the US National Institutes of Health, New England Journal of Medicine, Volume 353:1621-1623.

I don’t think we can continue to do what we’re doing now- pouring money into old ways of doing things when it comes to developing drugs, ways that are costly and not as efficient and effective as we can be. In too many places, discoveries are made using advanced sciences, but when they are brought up to the preclinical stage we start applying technologies that have been used for 50 or 60 years, such as animal toxicology. This is a completely empirical approach, even though we have technologies such as predictive assays that in selected cases can be more predictive and less costly to acquire than animal toxicology data. Scott Gottlieb, MD, Deputy Commissioner for Medical and Scientific Affairs, US FDA. Speech at PhRMA Scientific Regualtory Meeting, 29th November 2005.

Instead, in this and other areas of drug development, we should be adopting approaches that increase the use of mechanistic data in preclinical and clinical research to actually intelligently target new medicines to patients who are likely to experience more of the benefits and fewer of the side effects of a new drug. Scott Gottlieb, MD, Deputy Commissioner for Medical and Scientific Affairs, US FDA. Speech at PhRMA Scientific Regualtory Meeting, 29th November 2005.

In short, drug development has to be moved from empirical process to a more scientific process, just as the discovery and early development phase of drug creation has moved to be less trial-and-error and more deliberate and scientific. Scott Gottlieb, MD, Deputy Commissioner for Medical and Scientific Affairs, US FDA. Speech at PhRMA Scientific Regualtory Meeting, 29th November 2005.

Most medical researchers rarely, if ever, see patients. Most who argue for the necessity of the pyramid of discovery, with biochemistry and genetics at the base and clinical research at the apex, work at the base themselves [2]. However, many of the major discoveries that have had a direct impact on clinical practice arose from clinical disciplines rather than from generic biomedical approaches— consider hip replacements, cataract surgery, the importance of Helicobacter pylori, phototherapy, in vitro fertilisation, and minimally invasive surgery [4]. In the biomedical model, these successes are brushed aside as being of historical interest only. From finding genes to gene therapy and stem cell therapy, both the public and research community itself are fed a biased view of medical advances. Cancer cured (in mice) again. Jonathan Rees, Public Library of Science Medicine, April, Volume 2, Issue 4, e111.


The following quotes are all taken from: Keith Matthews & colleagues, Animal models of depression : navigating through the clinical fog, Neuroscience and biobehavioral reviews, Animals models of depression and antidepressant activity, vol. 29, no 4-5 (1 p.1/4), pp. 503-513.

- Modelling human mental disorders in experimental animals is fraught with difficulties. Depression models generally lack both clinical and scientific credibility and have, thus far, failed to inform treatment strategies previously acquired through serendipity.

- In light of these findings, we therefore pose two questions: if depression is infrequently (or even rarely) a consequence of sustained hypercortisolism, what is the biology of the relationship between psychosocial adversity and depression? Also, what is the validity and relevance of the wealth of studies modelling such processes in animals where the focus is almost exclusively on corticosteroid function and regulation?

- It is, therefore, an article of faith that the neural substrates underpinning certain behavioural and cognitive phenomena in experimental animals are the same as in humans.

- Many of the core features of depression may be ‘unmodellable’ in experimental animals.

- As one enters the ‘real world’, it becomes apparent that it is almost impossible to control not only the variables manipulated in the lab, but also the variables that cannot be modelled in animals—cognition, emotion, social behaviour, relationships, etc.

- Brain imaging consistently draws our attention to subregions of the prefrontal cortex as key structures whose altered function is associated with depression. How do we model such function in the rat? Although the rat may have a prefrontal cortex, the homology is highly controversial.

- There seems little prospect of using animals to model those features, which rely on a verbal description of a subjective experience (for example, suicidal ideation, guilt, lack of self-confidence, and low self-esteem).

2004

In many cases, developers have no choice but to use the tools and concepts of the last century to assess this century’s candidates. As a result, the vast majority of investigational products that enter clinical trials fail. Often, product development programs must be abandoned after extensive investment of time and resources…Often, developers are forced to use the tools of the last century to evaluate this century’s advances. US FDA, Innovation or Stagnation: challenge and opportunity on the critical path to new medical products.

The contribution of animal studies to clinical medicine requires urgent formal evaluation. Pound et al, Where is the evidence that animal research benefits humans? British Medical Journal, 328:514-517.

2003

Does the use of animal models of disease take us any closer to understanding human disease? With rare exceptions, the answer to this is likely to be negative. David F Horrobin, Nature Reviews Drug Discovery 2, 151 - 154.

Animal models - represent nothing more than an extraordinary, and in most cases irrational, leap of faith. David F Horrobin, Nature Reviews Drug Discovery 2, 151 - 154 (01 Feb 2003)

One must conclude that most predictions of near term human benefit are not only overblown but are actually fraudulent. David F

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