Thursday March 21, 2019
On, 14 March 2019, Chris Magee of Understanding Animal Research posted an article titled: Ricky Gervais doesn't understand animal research. In it, Magee stated:
'The ability of the model to find a ‘true negative’ reaction is for dogs 94%, mice 95.6%, rats 97.9% and rabbits 99.2%. However, certain species make good or poor models for different types of compound and it was discovered long ago that if something was toxic in a rodent and non-rodent model then it would almost certainly be toxic in a human. This is why regulatory authorities require testing in two species before clinical trials can start.'
As the above is stated without evidence it can be dismissed without evidence. That having been said, around 90% of drugs that pass animal tests fail in clinical trials for the reasons of efficacy and toxicity, the very reason animal models are used in testing. (1-12) Furthermore, many drugs do make it through animal testing as described above only to make it to market and seriously harm humans. (13-18) University of Utah press release discusses (17): “Because of undetected toxicity problems, about a third of prescription drugs approved in the U.S. are withdrawn from the market or require added warning labels limiting their use.” (16) So not all toxicities are seen during clinical trials when 90% of all drugs fail. Therefore, the ultimate failure rate of drug that have passed animal tests and that were developed in animal models is greater than 90%.
The second failure is the idea that drugs would then be dangerous in humans. Animals are used in testing to determine if a compound is safe enough to be given to human volunteers – no drug advances from the animal lab straight onto the shelves at the chemist. The animal test is not generally for determining whether it will be effective, just that it’s safe. Three rounds of testing in humans take place before the so-called ‘stage 4’ where the drug is rolled out to the wider human population.
This is controversial in drug development with some animal modelers claiming toxicity is performed simply to ensure safety in Phase I-III human clinical trials and others stating it is to ensure safety of humans in general. Regardless, the FDA is on record stating that 9 out of 10 new medicines fail to pass human/clinical trials because animal tests cannot predict outcomes in humans. 
The position that toxicity testing is only designed to protect people participating in first-in-man (FIM) trials is then followed by the claim that since so few people are injured during these trials animal models of toxicity must be effective. There are many problems with this logic. First, most of the time results from FIM trials are not released to the general public. The results are proprietary and Pharma does not want them released and, under current law, they have the right to not release them. Therefore, meta-analyses and systematic reviews that summarize the current scientific literature are of questionable value as it is the unpublished reports that would contain the damning evidence. So, Magee’s claim is an example of the fallacy of insufficient statistics and the animal modelers are using it to make a claim that is an example of the argument from ignorance.
Second, there are examples of people being harmed from FIM trials. Speaking of toxicity trials for new drugs in humans, an unnamed clinician quoted in Science stated: “If you were to look in [a big company’s] files for testing small-molecule drugs you’d find hundreds of deaths.” (19) This brings us back to burden of proof. It is naïve or disingenuous to think the burden of proof for assessing FIM trials is on the public without all the data. If animal modelers want us to think that FIM are remarkably safe then show us all the data. As society does not have access to all the data, quotes like the above in Science are damning. And there have been disasters that went public.
The traditional dose-escalation regimen is a cautious approach, designed to minimize risks to FIH trial participants. Risks are inevitable, however. A good assessment of the risks comes from a review of National Cancer Institute (NCI) phase I trials conducted from 1991-2002. Reviewers found that 15 percent of subjects in phase I trials of single chemotherapy agents experienced serious but nonfatal toxic events.95 Reviewers also found a toxicity-related death rate of .49 percent for FIH trials involving a single chemotherapy agent.96
95. Horstmann E, et al. Risks and Benefits of Phase I Oncology Trials, 1991 through 2002. New England Journal of Medicine 2005;352(9):895–904. [PubMed: 15745980]
96. Id. For another evaluation of risks and benefits in phase I oncology trials, see Roberts TG, et al. Trends in the Risks and Benefits to Patients with Cancer Participating in Phase I Clinical Trials. JAMA 292 (17)2004;:2130–2140.2140 [PubMed: 15523074] (20)
A major factor complicating risk analysis in FIH trials is the difficulty of making accurate predictions from preclinical laboratory research on human tissues and animal studies of the likely effect of the investigational agent on humans. According to Rebecca Dresser, risk analysis based on preclinical research can fall short in three ways. It may fail to predict human risks, leading to adverse effects in human trials – one example being the TGN1412 trial. It may predict clinical benefits that then fail to materialize for human subjects. And it may predict nonexistent risks in humans with the result that a potentially useful agent is discarded. (Dresser 2009)
Extrapolating from laboratory and animal studies is a complex process under all circumstances, but even more so in proposed FIH trials which usually lack data from comparator studies in humans to help guide the analysis. Although an effort is usually made to choose species based on their similarities to the human biological response under study, there may not be appropriate animal models that accurately replicate the human disease. Moreover, there are significant differences between human and animal physiology. Given the limitations of animal models of many diseases and differences between human and animal physiology, toxicological studies in animals may be poor at predicting toxicity in humans. (Lavery 2011) For similar reasons, the ability to show proof-of-principle in preclinical research, whether in the in vitro or the animal studies, does not provide a therapeutic warrant for humans . . . (Anderson and Kimmelman 2010)
To lower risk in Phase I trials, subjects usually receive a low dose of the investigational agent, and if that level of exposure appears safe, then the dose is gradually increased with each cohort until investigators determine the maximum tolerated dose. This approach, however, is not risk-free, especially when the trials recruit seriously ill patients.
A review of all non-pediatric Phase I trials conducted by the National Cancer Institute between 1991 and 2002, a total of 460 trials involving 11,935 participants, about one quarter of which were FIH trials, found that 15 percent of subjects in trials of single chemotherapy agents experienced serious but nonfatal toxic events. There were 58 deaths (a death rate of .49 percent) that were determined to be at least possibly related to the treatment. The toxicity related death rate in these trials was 0.26 percent. Rates of response and toxicity varied among the various types of Phase 1 oncology trials but the data for FIH trials were not separately computed.(Horstmann et al. 2005) It is difficult to know whether these data can be generalized to other types of trials. (21)
But if the reason for animal testing is to keep volunteers safe in clinical trials, then they are failing as the two main reasons drugs fail in clinical trials are efficacy and safety. (22-31) Moreover, severe side effects are not detected in clinical trials due to the limited nature of Phase II and III clinical trials due to the fact that they are so expensive. (32, 33) This leads to drugs being released to the market and causing severe harm in patients.
It’s illegal to use an animal if there’s an alternative,
This law is routinely ignored in reality as 1) regulatory agencies are comfortable with the status quo of using animals and 2) if they acknowledged how nonpredictive animal models are they would have to further acknowledge that using a magic 8-ball would do as good of a job. See Here's Why Vanda Pharmaceuticals Is Sinking Today.
Testing on animals was mandated as compulsory by the Nuremburg Code after the Nazis, who were anti-vivisection, tested on humans instead.
I have refuted this many times. See The Nuremberg Code subverts human health and safety by requiring animal modeling.
But it is also illegal not to test a potential new medicine using animals before it is given to human beings. It’s the law because it works to keep us safe and has done so for more than 50 years.
No, actually it hasn’t. The scientific literature is replete with scientists saying animal modeling does not work in terms of safety and efficacy. (19, 22-28, 30, 33-62)
Magee is right when he says it takes more words to correct errors than it took the person who wrote the errors: “it’s just so easy to throw out an ignorant comment and it somehow falls to the person with the facts to set the record straight.”
Biology has been under assault from the same detractors for years – Young-Earth creationists, anti-vaxxers and anti-vivisectionists are not new, nor have their tactics changed over the past 150 years. There are always the false claims about efficacy, as if researchers would deliberately sabotage their own careers doing experiments that wouldn’t work. There’s the ‘follow the money’ argument that posits that the world’s regulators, academics, learned societies, industry bigwigs and all professional toxicologists have been duped by rat breeders wishing to sell them rats. There’s the false danger argument – did you know vaccines have mercury in them?!
This is a classic example of the fallacy of poisoning the well.
Mr Gervais seemed to grasp this point during his now-ironically titled S.C.I.E.N.C.E. tour, but beliefs don’t trump facts. If you’re too busy for facts, try a shortcut and ask ‘What does every serious scientific institution in the world think?’ What does the Royal Society think? What does the FDA think?’ To be on the wrong side of this argument is literally to argue against cancer treatments, insulin and whatever’s coming next. This is far too important a moral question be this intellectually lazy about.
This uses the fallacies of appeal to fear and argument from authority. Every institute that profits from animal modeling, or has a different kind of vested interest, supports animal modeling. What a shock! And when Magee asks 'what does the FDA think?', remember the FDA acknowledges that 90% of new medicines do not reach human patients because animals cannot predict outcomes in humans. (4)
The empirical evidence overwhelmingly favors the position that animal modeling has no predictive value for human response to drugs and disease. The studies that claim otherwise are cherry-picked or misrepresented. But what really closes the case against animal modeling is Theory. Just as Darwin’s Theory of Evolution explained why creation was not necessary and Einstein’s Relativity Theory proved Newton’s physics was not completely accurate, so Trans-Species Modeling Theory (TSMT) explains why animals will never be of predictive value for human response to drugs and disease. (63) This is what animal modelers want to avoid debating in a fashion described below. Most members of the scientific community do not have a broad enough science background to understand TSMT and it is unreasonable to ask the general public to understand it. But, experts in the appropriate fields can and will understand it and this will end animal modeling as used for predictive models for humans.
Using fallacies, ignoring science, and relying on peoples’ cognitive biases have worked well for the animal model community: their scientifically unviable paradigm persists. As long as the animal model community can continue to use these tactics to mislead the unsuspecting and scientifically illiterate public, they will continue to make money from animal modeling. What is needed is a peer-reviewed debate as described in: Greek, Ray, and Lisa Kramer. 2019. "How to Evaluate the Science of Non-human Animal Use in Biomedical Research and Testing: A Proposed Format for Debate." In Animal Experimentation: Working Towards a Paradigm Change. Human-Animal Studies. Volume 22., edited by Kathrin Herrmann and Kimberley Jayne, 65-87. Boston: Brill.
FLOE in the UK has proposed this in Parliamentary EDM 66. If the animal model community is so confident that animals are necessary for medical science to advance, they should jump at the opportunity to have their position judged by experts in the various scientific fields upon which animal modeling is based on. But the animal modelers are not doing so.
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