Tag Archives: animal tests

Nine out of ten Statistics are taken out of Context

This guest post is by Professor Robin Lovell-Badge, who is head of the division of Stem Cell Biology and Developmental Genetics at the Medical Research Council National Institute for Medical Research in London. This is a very clear and thorough debunking of a common animal rights myth where they suggest that because nine out of ten drugs that pass animal tests still fail to be approved, that animal tests must not work – In this post Prof Lovell-Badge explains the true meaning of these misused and misunderstood statistics. This post is also appearing on other websites including www.understandinganimalresearch.org.uk.

Facts without context

Those opposed to animal research often point out that most drugs that pass the legally required toxicology tests in animals go on to fail in human clinical trials. They then go on to suggest that this shows that animal research does not work, or that it is proof that animals are not accurate models for humans.

However, this is misleading without an understanding of the relevant context and the reasons for the animal safety tests. Ironically, the figures cited by many animal rights activists are actually drawn from industry and are intended to explain the expense of developing safe and useful medicines.

The most frequently used statistics are

  • 90% drugs tested on animals fail” – British Union for the Abolition of Vivisection
  • 92% of drugs fail in clinical trials, having successfully passed through animal studies” – Safer Medicines Trust
  • “In fact according to the FDA’s research, nine out of ten drugs deemed successful in animal tests fail in human clinical trials” – Humane Society International

The main sources of this information come from the US Food and Drug Administration (FDA). In 2006, Mike Leavitt said:

“Currently, nine out of ten experimental drugs fail in clinical studies because we cannot accurately predict how they will behave in people based on laboratory and animal studies,” said Health and Human Services Secretary Mike Leavitt.

The 92% statistic comes from an earlier report which showed only 8% of those drugs passing animal testing stages would go on successfully to be FDA approved.

“For example, a new medicinal compound entering Phase 1 testing, often representing the culmination of upwards of a decade of preclinical screening and evaluation, is estimated to have only an 8 percent chance of reaching the market.” – Challenges and Opportunities Report, FDA, 2004

Are the figures right?

To help break down these statistics, it is useful to look at the success rates at each stage (source). In the diagram below the red percentages show the proportion of drugs that move from one stage to another – so 64% of New Molecular Entities (NMEs – essentially new drugs) will pass the animal tests (preclinical studies) and be moved into Phase 1 clinical trials in humans. Looked another way, animal experiments remove 36% of the potential drugs from moving onto the next stage. This is almost certainly a good thing as it avoids humans being given drugs which are likely to be toxic to them. The percentages at the bottom look at the percentage chance that a drug that has made it to that stage will make it all the way – so of all the drugs that make it to Phase 2 clinical trials, 12% will be approved by the FDA (and 88% will fail).

NME = New Molecular Entity. This means a possible drug that is going through trials.

NME = New Molecular Entity. This means a possible drug that is going through trials.

The first thing to note is of those drugs which pass animal tests, 94% will fail during human clinical trials stages (Phases 1 – 3)*.

* number of drugs which have passed Phase 3 clinical trials ÷ number of drugs which have passed just animal tests = 1.2 ÷ 19.4 = 6.2% of drugs which reach Phase 1 trials are eliminated by Phase 1-3 clinical trials. 100 – 6.2 = 93.8% fail.

 

So the failure rate is actually higher than even the animal rights organisations suggest (since they are using data from before 2006). Is this damning for animal research?

Consider that of all the drugs which pass Phase 1 clinical trials in humans, 86% will fail in later stage human trials**. Yet, we do not hear activists suggesting that humans are an entirely inappropriate model for drug development (though we should note that one human is not a perfect model for another).

** number of drugs which have passed Phase 3 clinical trials ÷ number of drugs which have passed Phase 1 trials = 1.2 ÷ / 8.6 = 14% of drugs which pass Phase 1 trials are eliminated by Phase 2-3 clinical trials. 100 – 14 = 86% fail.

Facts with context

Here is where it is important to understand a little about the drug development process.

Before the preclinical animal tests there are a large number of pre-preclinical non-animal tests done on all manner of research tools including computer models, automatic screening, cell cultures, microbial studies and more. These methods are used to (relatively) cheaply remove many potentially toxic, or obviously non-starting drugs from reaching the more expensive animal testing stage – greatly reducing the amount of animal research required for a drug to reach market.

So contrary to animal rights claims of alternative methods being better, the truth is that 94% of drugs that pass animal AND non-animal preclinical tests will fail in human tests.

So rather than damn just the animal tests, have animal rights activists managed to damn all of preclinical research? In short, no.

The role of preclinical animal tests is to check if the drug offers any potential therapeutic value and, importantly, if it is safe enough to move to Phase 1 trials in humans. This does not even mean free of all side effects, but to learn whether a drug can safely be given to humans and at what approximate dosage.

If you want to know how truly successful animal tests are, consider that in over 30 years there has not been a single death in a Phase 1 clinical trial in the UK. The last major incident was in 2006 in the Northwick Park trials where 6 people suffered extreme side effects in a Phase 1 clinical trial – though it should be noted that TGN1412 was a very novel type of molecule which was poorly understood. Considering that there are normally over 200 Phase I clinical trials each year in the UK (each involving multiple people), animal testing has been exceptionally effective at keeping dangerous drugs away from people.

Even Phase 1 clinical trials in humans are not intended to check for efficacy, but rather to assess whether a drug is safe enough to be tried in a larger number of patients (who are suffering from an illness the drug is intended to treat).

Furthermore, when a drug is licensed for use, it is on the basis of the clinical trials in humans, not the preclinical animal tests which exist to ensure that a drug is safe enough to move into Phase 1 trials. So when animal rights activists claim that adverse drug reactions can be blamed on animal tests approving the drug, remember that it is the clinical trials in thousands of people which provide the evidence of its safety.

Professor Robin Lovell-Badge

Head of the Division of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research, London

Several Hundred Pro-Test for Science

On a beautiful sunny day in Los Angeles, Pro-Test for Science organizers arrived at the junction of Le Conte and Westwood, on the edge of the UCLA campus, with armfuls of placards in support of animal research. Within ten minutes every placard had found a new owner as hundreds of scientists, students and members of the public showed up to support the cause. Those gathering chatted together, sharing their reasons for attending the rally.

Marchers Gather

Marchers Gather at the edge of the UCLA campus

Those participating were not limited to the UCLA community. Faculty from University of Southern California, California Institute of Technology, and California State University – Los Angeles, all came out to demonstrate their support for lifesaving medical research using animals. Soon the chants began to ring out – “Penicillin? ANIMAL RESEARCH! Insulin? ANIMAL RESEARCH! Vaccines? ANIMAL RESEARCH! Anaesthetics? ANIMAL RESEARCH!” A short while later, when the crowd had swelled further, the rally set off towards the center of the UCLA campus.

The marchers begin to walk towards the center of the UCLA

"What do we need? ANIMAL RESEARCH! When do we need it? NOW"

The mood was one of excitement and passion. Those participating exchanged ideas for public outreach in the future – sharing the best of ways of explaining to the public the clear connection between animal research and medical benefits. The rally continued to snake along  Westwood and up towards Wilson Plaza.

Those at the front were unable to see the back of the rally!

"No more threats, no more fear. ANIMAL RESEARCH NEEDED HERE"

As the rally turned into Wilson Plaza, passing the top of Bruin Walk, hundreds of students turned their heads towards the march, many shouting words of encouragement or joining in the rally.

"Cures for cancer, what's the answer? ANIMAL RESEARCH! ANIMAL RESEARCH!"

Eventually the tail end of the rally reached the destination (some time after the front end due to the length), and Tom Holder brought the crowd together for a picture perfect moment of solidarity before shouting “What do we need?”. “Animal Research” replied the hundreds of voices in unison.

David Jentsch at the Pro-Test rally 2010

Prof. David Jentsch

Holder then introduced the first speaker, Prof. David Jentsch – founder of Pro-Test for Science and member of the Speaking of Research committee – who took the microphone to rapturous applause. David spoke of the progress of Pro-Test for Science, and the struggle against animal rights extremists in UCLA. He took the time to thank each of the individuals who had made the 2010 rally possible eliciting a cheer from the crowd as each name was called. Jentsch then passed over to Tom Holder, founder of Speaking of Research.

Tom Holder at the Pro-Test for Science Rally

Tom Holder

Holder thanked the crowd, insisting that UCLA were winning in their battle against extremists. However he warned the crowd against complacency – saying that public outreach was the only way to win this battle in the long run. Holder also announced the success of the Pro-Test Petition, which had gained 11,621 signatures over the previous year (including Nobel Prize Laureates, and every chancellor in the UC system, including UC President Mark Yudof). He finished by announcing the presentation of the signatures to Dr. Kevin Quinn,  Dr. Michael Steinmetz.

Dr. Kevin Quinn

Dr. Quinn, the Chief of Behavioural Science and Intergrative Neuroscience at the National Institute of Mental Health (NIMH), accepted one copy of the petition on behalf of NIMH. Quinn spoke of the important role that animal research has in our understanding of Mental Health problems:

Animal research conducted in a humane, ethical and responsible manner is absolutely critical … to understand, treat and cure mental disorders

.

Dr. Michael Steinmetz

Dr. Michael Steinmetz, program director of the National Eye Institute, talked of the medical breakthroughs in vision. He spoke particularly of Leber’s congenital amaurosis, a form of blindess which affects thousands of people across the United States. Through research in mice and then dogs (Briards), scientists found a way of inserting a gene into the eye through a virus, which could corect the problem.

“The National Eye Institute supports strongly the use of appropriate animal models in research, not just for the big clinical advances but for the many, many years of basic science that it takes to discover the underlying biological principles

Scott Waugh

Jentsch then returned to the stage to introduce UC Executive Vice-Chancellor, Scott Waugh. Waugh offered his continued support to researchers at UCLA, mentioning that the Pro-Test for Science movement has played an important role in bolstering support for research. He congratulated Jentsch and Ringach for organizing the February pabel debate, explaining that “violence, threats and other criminal activity are never a viable alternative to dialogue”.

Jentsch and Holder finished the rally by talking of the importance of continued education and outreach.

They're Pro-Test. Are you?

Pompe disease – a starring role for animal research

The new Harrison Ford film, Extraordinary Measures, hitting US cinemas from 22 January, is a fictionalised account of the development of a treatment for Pompe disease, a rare genetic disorder. Pompe disease (glycogen storage disease type 2, acid maltase deficiency) is an enzyme deficiency with devastating effects – progressive muscle weakness and, in the severe infantile form, gross enlargement of the heart. Until fairly recently, the infantile form of the disease was invariably fatal within the first year of life. Now, however an effective treatment is in place.

Extraordinary Measures

While the increased awareness that the film’s fictional account brings is very welcome, the real story of how that treatment came about is a fascinating one (1) and laboratory animals play a starring role. The long road to a treatment started in 1932 with the first observation of the disease by Dr JC Pompe, after whom it is named. Pompe described accumulation of glycogen in muscle tissue, which was a puzzle, as the enzymes involved in the usual metabolism of glucose and glycogen were all present and correct.  The solution to this puzzle had to wait until Christian de Duve’s 1974 Nobel Prize-winning discovery of lysosomes in 1955. These cellular compartments or organelles are the ‘recycling units’ of animal cells. They have an acid environment and their own specific set of enzymes for breaking down cellular components.

De Duve was carrying out ‘blue skies’ research, with no thought of direct medical application.   However, as so often in research, a breakthrough in our basic understanding of biology led to medical applications. In this case, de Duve’s colleague Henri Hers realised that the deficiency of a lysosomal enzyme (alpha glucosidase) for the breakdown of glycogen would explain the symptoms of Pompe disease. This proved to be the case, and Hers established the principle of lysosomal storage diseases, of which around 40 have now been described, in 1965.  Before moving on, let us note the role of laboratory animals in this breakthrough. I wrote to Professor de Duve and asked what part the use of animals had played in his work and he replied that “We would not have been able to make the discoveries we made without an extensive use of laboratory animals.”(2)  – a statement confirmed by his Nobel Prize lecture.

Having discovered the basis of Pompe disease, the next milestone was to develop a treatment. This proved to be very difficult, largely due to the lack of animal models.  A recurring refrain from the animal rights lobby is that if the humane use of animals in medical research was banned, scientists would soon find other ways to ensure medical progress. That comforting belief is belied by the series of attempts, some of them pretty desperate, to treat terminally ill children over the next 25 years. None of them worked.

The next great leap forward came from The Netherlands in 1990 and relied on the use of laboratory mice.  Enzyme replacement therapy (ERT)  had long been suggested as a potential treatment for lysosomal storage diseases but had never succeeded. In the case of Pompe disease, where large amounts of enzyme were needed in the muscle, introduced enzyme was simply soaked up by the liver. Two Dutch scientists, Arnold Reuser and Ans van der Ploeg, had the idea that phosphorylated enzyme would be taken via by the mannose-6-phosphate receptors in lysosomes, allowing the enzyme to be targeted.

However the supply of phosphorylated enzyme was small – nowhere near enough to treat a sick child. How could efficacy be demonstrated, in the absence of an animal model? In an ingenious experiment (3), they used specific monoclonal antibodies to demonstrate that when bovine phosphorylated alpha glucosidase was introduced to mice, it was taken up by heart and skeletal muscle lysosomes and caused a significant increase in enzyme activity – a 43% increase in skeletal muscle and 70% in the heart. An increase that, if repeated in humans, would result in the level of enzyme found in the healthy population.  With characteristic understatement, van der Ploeg et al concluded “…we think that the original idea of enzyme replacement therapy for treatment of lysosomal storage diseases deserves new attention.” At last, thanks to this ground-breaking work, a treatment for Pompe disease was a real possibility.

Now that there had been ‘proof of principle’ all that was needed was for a pharmaceutical company to spend millions of dollars in developing a treatment. Understandably perhaps, given the rarity of the disease and the inability to demonstrate actual efficacy, there was no immediate rush.   Fortunately, at this point two animal models became available that allowed scientists to demonstrate that not only did the phosphorylated alpha glucosidase make its way to the lysosomes, it also had a beneficial effect.

From 1998 onwards, transgenic mice with Pompe disease, developed in Rotterdam and elsewhere, were used to demonstrated the efficacy of alpha-glucosidase enzyme.  At the same time the potential of ERT was also illustrated, more dramatically perhaps, by YT Chen at Duke University, using quail. The quail had the same enzyme deficiency as found in humans, resulting in muscle weakness. After injection with the enzyme, they recovered to the extent of one subject actually flying around the lab (4). The evidence was therefore now pretty convincing – it was time for human trials.

The big problem was in producing enough enzyme for humans, even for babies. This required substantial industry investment. Two rival approaches were tried. A Dutch company, Pharming, produced the enzyme in the milk of transgenic animals for use in a trial led by Ans van der Ploeg, whose PhD research had led to the original breakthrough. The transgenic animal used was the rabbit, on the grounds that a human alpha-glucosidase-producing line could be established quite quickly. This work was used in a successful clinical trial, the results of which were published in The Lancet in July 2000 (5).

Another trail was carried out by YT Chen, using enzyme produced via Chinese Hamster Ovary (CHO) cell culture, by Synpac, a Taiwan-based company. This trial was also successful.

What follows next is a slightly convoluted story. The short version is that a third company, Genzyme, with an existing enzyme replacement therapy for Gaucher disease, bought out both Pharming and Synpac. In the end, they didn’t use either of the enzymes produced by these companies but developed their own, in-house CHO product, now marketed as Myozyme. This was a difficult decision – how could they decide which of the competing products should be invested in to produce a commercial treatment? The answer was what Genzyme called “The mother of all experiments” which compared the different products in transgenic Pompe mice. The result led to the availability of the treatment we have today.

However, the eventual production system is a technicality that need not concern today’s patients. Their concern is that an untreatable, terminal illness is now treatable. If you go and see Extraordinary Measures do bear in mind the starring role that doesn’t appear in the cast list – that of the mice and quail that made this treatment possible.

Kevin O’Donnell

Edinburgh

1. http://pompestory.blogspot.com
2. Letter from Christian de Duve to Kevin O’Donnell, 4 March 1997
3. Intravenous Administration of Phosphorylated Acid Alpha-Glucosidase Leads to Uptake of Enzyme in Heart and Skeletal Muscle of Mice http://www.jci.org/articles/view/115025
4.  Clinical and metabolic correction of pompe disease by enzyme therapy in acid maltase-deficient quail http://www.jci.org/articles/view/1722/pdf
5. Recombinant human alpha-glucosidase from rabbit milk in Pompe patients http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02533-2/fulltext#article_upsell (free registration required)

Biographical note.

I should declare an interest. I am a professional scientist, however my involvement with Pompe disease dates from the diagnosis of our first child, Calum, with infantile Pompe disease in 1993. At that time the disease was still untreatable and Calum died at 8 months of age. Following that I had the great privilege of participating in an international community of patients and scientists that championed the development of a treatment for Pompe disease. They don’t appear in the cast list of the film either, or the book on which it is based The Cure by Geeta Anand. This prompted me to write the real story down – I think it’s a better story than either rthe book or the film though not, sadly, as well written. Your comments welcome at http://pompestory.blogspot.com You can find out more about Pompe disease from the following sites:

International Pompe Association www.worldpompe.org
Acid Maltase Deficiency Association www.amda-pompe.org
UK Pompe Group www.pompe.org.uk
Genzyme www.pompe.com

Fighting the Flu

Unless you have been living as a hermit in a cave* for the past week you will be aware that the world’s medical services are on high alert following the emergence of swine flu in Mexico, a new strain of the Influenza A/H1N1 virus that has now killed more than 160 people. While there is now evidence that swine flu may not lead to the number of deaths worldwide that were initially feared, this is still a serious situation and it is only right that governments and the UN are taking all necessary precautions.

Swine Flu

This is a good time to see how animal research contributes to the development of treatments and vaccines that are vital tools in ongoing efforts to control the damage that this virus can do. On Wednesday the US Centers for Disease Control and Prevention (CDC) announced the welcome news that swine flu is sensitive to the neuraminidase inhibitor antiviral medications zanamivir (Relenza) and oseltamivir (Tamiflu), so these drugs will be effective in treating swine flu infection. These anti-virals work by binding to and blocking the activity of the enzyme neuraminidase (the N in H1N1) that is found on the surface of the flu virus and whose activity is required for the virus to infect cells. This news is doubly pleasing since there had been concern that swine flu might have evolved resistance to Tamiflu (but not to Relenza), but so far it appears that this has not happened and it is still a good treatment.

Animal research played an important role in the development of both Relenza and Tamiflu. In particular they were key during the later stages of the process as candidate neuraminidase inhibitors that had performed well in in vitro anti-viral tests were evaluated for their ability to kill the virus in vivo, and for their pharmacokinetic profile and toxicity, before being modified and then re-evaluated until two neuraminidase inhibitors were produced that had the right properties to justify evaluation in human clinical trials (1,2). In the case of Tamiflu the animal stuidies lead to the development of a prodrug that is metabolized in the body to produce the active anti-viral, while with Relenza the scientists identified a modification to the drug that greatly enhanced its anti-viral activity while also slowing down its breakdown in the body. In addition to rodent models of flu infection some of these studies also involved ferrets, animals that are naturally prone to infection with many of the influenza viruses that humans suffer from and in which the course of the virus is almost identical, making them a very valuable model for studying the disease and developing new treatments.

Of course in the longer term it would be better to develop a vaccine against swine flu, and efforts to do so are already underway at research laboratories in the US and UK. This will probably take months, but the vaccine will hopefully be completed in time to reduce the impact of a pandemic. The time required to develop a vaccine with the currently available flu vaccine technology , the same that is used to develop the vaccines against seasonal flu that you will probably be familiar with, is a consequence of the fact that they only provide protection against one strain of the virus. This is because these vaccines direct the immune system to target the haemagglutinin (the H in H1N1) and neuraminidase proteins on the surface of the virus, but these proteins frequently mutate and can become invisble to the immune system again, so a new vaccine corresponding to the new version of haemagglutinin or neuraminidase must be developed.

Consequently several groups of scientists around the world are now working on “universal” influenza vaccines that it is hoped will provide protection against a wide range on influenza strains. Last year there were reports on the successful completion of early clinical trials of one such vaccine developed by Acambis, a vaccine that directs the immune system to target a protein in the virus envelope named matrix protein 2 (M2e) whose structure is highly conserved across different strains of the influenza A virus. Studies on mice were crucial to the initial development and optimization of this vaccine and to the later demonstration that it could provide protection against a range of influenza A strains (3,4), leading to the decision to test it in human clinical trials. It’s clear that animal research has made important contributions to both the treatments that are available to fight swine flu now, and to ongoing efforts to produce new vaccines that will hopefully help us to avoid flu pandemics in the future. As to the wider situation we are pleased to see that President Obama has appointed the leading cancer biologist and Nobel Prize laureat Harold Varmus and the human geneticist and former leader of the mouse genome sequencing project Eric Lander to the President’s Council of Advisors on Science and Technology (PCAST). The advice provided by these two scientists, both of whom fully appreciate the great importance of animal research to medical progress, will no doubt be of great value to the President over the coming months, as the President himself said “our capacity to deal with a public health challenge of this sort rests heavily on the work of our scientific and medical community”. His is a view that we are happy to share.

* Though if you believe some of the more alarmist newspaper reports hiding in a cave might not be such a bad idea.

Regards

Paul Browne

1) Eisenberg E.J. et al. “Penetration of GS4071, a novel influenza neuraminidase inhibitor, into rat bronchoalveolar lining fluid following oral administration of the prodrug GS4104.” Antimicrob Agents Chemother. Volume 41(9), Pages 1949-1952 (1997) PubMed Central: PMC164042

2) von Itzstein M. et al. “Rational design of potent sialidase-based inhibitors of influenza virus replication” Nature. Volume 363(6428), Pages 418-23 (1993) PubMed: 8502295

3) Neirynck S. et al. “A universal influenza A vaccine based on the extracellular domain of the M2 protein.” Nature Med. Volume 5(10), Pages 1157-1163 (1999) PubMed: 10502819

4) De Filette M. et al. “Universal influenza A vaccine: optimization of M2-based constructs” Virology Volume 337(1), Pages 149-161 (2005) PubMed: 15914228