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On “concordance” and “discordance”
- Marco Mamone-Capria (10 January 2007)
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Medical Progress: thanks to clinical research, not animal research
- Kathy A Archibald (23 January 2007)
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The failure of animal research
- Marlene A. Thompson (30 January 2007)
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A Broader View of Animal Research
- Timothy I. Musch, Robert G. Carroll, Armin Just, Pascale H. Lane, and William Talman (31 January 2007)
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Animal models of human disease; of mice and menace
- Janusz A Jankowski, Lea-Anne Harrison and Janusz Jankowski. (31 January 2007)
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An uncited paper
- Neville W Goodman (7 February 2007)
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Marco Mamone-Capria, Researcher University of Perugia, 06123 Perugia
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In their valuable paper Perel et al. [1] present an outline of a systematic review [2] concerning the degree of agreement between animal experimentation (or “vivisection” [6, p. 30, n. 1]) and clinical trials in six fields of medical inquiry: (a) thrombolysis in acute ischaemic stroke (AIS), (b) bisphosphonates to prevent and treat osteoporosis, (c) antenatal corticosteroids to prevent neonatal respiratory distress syndrome, (d) corticosteroids in traumatic head injury, (e) tirilazad in acute ischaemic stroke, (f) antifibrinolytics in haemorrage. The authors conclude that in cases (a), (b), (c) there was «concordance» or «similar outcomes», while in (d), (e), (f) there was not. Most disquietingly -- but not unexpectedly for whoever knew [3] and [4], or bothered to examine with some care a sample of the vivisectionist literature -- in all six cases the quality of the animal experiments examined turned out to be «poor». This was indicated by violation of such basic requirements as randomization, adequate allocation concealment, and blinded assessment of outcome (cf. table 1 in [1]). Although this dire balance sheet is in itself a sufficient refutation of the standard case for animal experiments as a scientific (rather than psychological) foundation for clinical research, a closer examination of the meaning of “concordance” and “discordance” is rewarding. 1 “Concordance” In case (a) the authors found evidence of publication bias (i. e. articles with positive results more likely to have been published), which implies that the available data are statistically hard to make sense of. Indeed, a general difficulty facing systematic reviewers is that «The proportion of the work that gets published in a form that is available to the public (rather than just being available to industry and the regulatory authorities) is unknown» [13]; a good idea would be to contact the regulatory agencies but, to cite the authors’ own example, the Home Office in United Kingdom has no accessible register of animal experiments licensed under the Animals Act 1986 [1]. In case (c) there was concordance as to reduction of respiratory distress syndrome in animals and in neonates, but not as to mortality, which was reduced in neonates and yet was increased in animal models, and significantly so in ewe models (the pooled odds ratio was 12.5, with 95% confidence interval 1.9 to 79.2, «with no evidence of significant heterogeneity [...]»). Clearly mortality is such a crucial parameter, that, for those who take animal experiments seriously, results in even one animal model indicating correlation of a treatment with increase in mortality should lead to immediate withdrawal of that treatment from clinical use and experimentation. For antenatal corticosteroids we know, from the clinical trials, that this decision would have resulted in the loss of human lives. The authors in their full report cite, as evidence of «lack of communication» between the animal experimenters and clinical researchers, the «conclusion of one animal head injury study that “timely high-dose dexamethasone treatment may help clinicians to manage head injury cases”», which was published six months after the publication of the CRASH trial. The CRASH trial had shown that this class of treatments actually increased mortality in head injury patients [2, p. 45]. While this example is enlightening as further evidence that animal experimentation, unaided by previous knowledge of what is the correct result that “must” be found, is no better -- and no less dangerous -- than divination, one should keep track, nonetheless, of the extent animal experimenters who “got it right” had read in their (perhaps suitably “elaborated”) data what they knew clinical investigators had already shown. For example, in the “concordant” cases (b) and (c), as the authors inform us in the full report, «The animal research continued after effectiveness in humans was established» [2]. This raises further doubts on the true degree and quality of the purported «concordance». Let us clear the ground from a possible misunderstanding, often lingering in the debate between supporters and critics of animal experimentation. That some degree of “concordance” between animal experiments and clinical trials will be found is no surprise at all. To say that animal experiments are unreliable, as indeed [1] confirms they are, does not mean that they give constantly the wrong indication. Were it so, they would be exceedingly useful, since by systematically denying what they indicate we should always get a correct answer to our medical questions. Unfortunately, life is not so easy, and here lies precisely the danger of all pseudoscientific practices [8]. 2 “Discordance” The discordance in cases (d) and (e) is particularly worrying, as animal experiments failed to show the increase in mortality in case (d) and the risk of death and dependency in case (e). This means that by relying on the “indications” provided by animal experiments lives have been lost. In case (e), however, the authors try to show that the discordance can be explained by using the results of “concordant” case (a). If successful, this attempt might vindicate, at least in one example, the image of animal experimentation as a potentially reasonable, self- correcting endeavor. But is it so? Let us see. According to the authors, the discordance in the tirilazad case between animal experimentation on AIS and clinical trials may have arisen from the difference in the time delays, between onset of AIS and treatment, in humans (median 5 hours) and in animal models (median 10 minutes). This suggestion (also advanced in [5]) needs to be carefully assessed. At a first level, the remark that excessive delay to treatment, particularly in the case of AIS, might reduce the efficacy of a treatment seems quite plausible. However, can the thrombolysis animal experiments, where there was “concordance”, be used as a sufficient ground to think that “similar” benefits (or lack of them) in animals and, respectively, humans are obtained with quantitatively “similar” delays to treatment? In fact, «there is some evidence that it might take many hours for damage to develop in human brains» ([5]). Moreover, as can be read in the complete report [2, p. 26], in the tirilazad experiments «there was no significant relationship between delay to treatment and efficacy», although «maximum efficacy was seen when treatment was given before the onset of ischaemia, with efficacy appearing to fall thereafter with time». Thus even after the systematic review ([1], [2]), the evidence for prescribing similar delays to treatment in animal experiments and in human trials in order to get clinically relevant animal data is far from unambiguous. It is a prudent bet that whatever lessons will be learned from the tilirazad failure -- and from the failure of more than 37 supposedly neuroprotective drugs tested in more than 114 clinical trials after encouraging results on animals [5] --, they will come from careful study of the human, rather than animal, data. In general, if one wishes to proceed in a truly scientific way, one cannot but refer to the mechanism of the pathological process and to the mode of action of the drug – if known. More precisely, if one can assume that (1) in both animal models and humans an essential component of the pathological process acts by the same mechanism and (2) with the same time scale, or otherwise with a known scale factor; and that (3) the mode of action of the drug in both animal models and humans is to interfere in the same way with that component of the pathological process, and to affect in the same way any other organs involved; then one might correctly draw from animal experiments likely conclusions about the efficacy and adverse reactions of the drug on humans. Once the argument is made explicit it is easy to see what the trouble is. The trouble is that even if we knew that (1) and (2) hold – and unfortunately this is hardly ever the case, also because of the well-known sensitivity of living organisms to small differences, both intraspecific and interspecific ([6, pp. 15-32]) –- still (3) can be assessed only after both the animal experiments and the human trials have been performed. To put it shortly, we can judge the correctness of the inference from animals to humans only with hindsight: “similarity” between animal data and clinical results is normally the effect of a posterior and largely arbitrary reconstruction. This means that animal experiments cannot be used to (scientifically) predict results on humans. And yet the assumption of predictive power is about the only justification of animal experiments which can boast some degree of public acceptance. 3 Combining data from different species A fundamental question which all systematic reviewers must face is how to combine results from different animal species in a way that is relevant to still another species. Two of the authors stated in 2002: «Consistent results across species and models would provide some reassurance that humans beings might respond in the same way» ([7]; see also [3]). What is the meaning of «across species»? In how many, or in which, species and strains should one get consistent results in order to be rationally (not merely psychologically) reassured? It is useful to remember that, among mammalians only, about 4,237 different species are known (I take the figure from a book published in 1994), and as already mentioned there are many cases (discussed for instance in [6] and [8]) where inconsistency occurs even inside one species, with outcomes depending on strains, sex of animals, food, cages, laboratory environment etc. Taking into account comorbidities, although prima facie reasonable, would only exponentially magnify the intractability of the problem. I am sure this point need not be belabored, at a time when huge resources are being invested in the development of drugs tailored on the genetic profile of the individual (human) patients. The main reason for such gigantic research effort is, of course, the recognition that most drugs are effective only on a minority -- sometimes a very small one -- of patients ([9], [10]). It is on this very basic issue that science and vivisection part ways. There is simply no scientifically validated procedure for combining data from experiments on different non-human species and to get information relevant to humans. The burden of the proof is on those who claim that such a validation has ever been provided. For example, as ECVAM (European Centre for the Validation of Alternative Methods) director Thomas Hartung recently stated, «The [animal] toxicity tests that have been used for decades are “simply bad science”» [11]. There is no reason to think that systematic reviews, in themselves, can remedy this situation. For all we know, to combine results from several species might be like the procedure used to solve the legendary problem of the length of the nose of the Emperor of China, as described by physicist Richard P. Feynman [11, pp. 295-6]: one asked Chinese people what they thought this length was, and then averaged answers. All very well -- except that no one in China had ever been permitted to see the Emperor. In conclusion, it is not surprising that animal experimentation does not inform human health care [3]: there is no known scientific way in which it could do that. The usefulness of systematic reviews of animal studies lies in bringing home this important truth, while the suggestion to adopt «an iterative approach to improving the relevance of animal models to clinical trial design» [1] seems in the light of all the available evidence unwarranted. References [1] Perel P., Roberts I., Sena E., Wheble P., Briscoe C., Sandercock P., Macleod M., Mignini L. E., Jayaram P., Khan K. S., “Comparison of treatment effects between animal experiments and clinical trials: systematic review”, BMJ, 15 December 2006 <www.bmj.com/cgi/rapidpdf/bmj.39048.407928.BEv1> [2] --, “Testing treatment on animals: relevance on humans”, <www.pcpoh.bham.ac.uk/publichealth/nccrm/PDFs%20and%20documents/Publications/JH18_Final_Report_May_2006.pdf> [3] Roberts I., Kwan I., Evans P., Haig S. “Does animal experimentation inform human healthcare? Observations from a systematic review of international animal experiments on fluid resuscitation”, BMJ, vol. 324, 23 February 2002, pp. 474-6. <www.bmj.com/cgi/content/full/324/7335/474> [4] Pound P., Ebrahim S., Sandercock P., Bracken M. B., Roberts I., “Where is the evidence that animal research benefits humans?”, BMJ,, vol. 328, 28 February 2004, pp. 514-7. <www.bmj.com/cgi/content/full/328/7438/514> [5] Green A. R., Odergren T., Ashwood T., “Animal models of stroke: do they have value for discovering neuroprotective agents?”, TRENDS in Pharmacological Sciences, vol. 24 (8), August 2003, pp. 402-8 [6] Croce P. Vivisection or science? An investigation into testing drugs and safeguarding health, London: Zed Books, 1999. [7] Sandercock P., Roberts I., “Systematic reviews of animal experiments”, The Lancet, vol. 360, August 24, 2002, p. 586. [8] Mamone-Capria M., “Pseudoscienza nella scienza biomedica contemporanea: il caso della vivisezione”, Biologi Italiani, June 2003, 33(6), pp. 10-27 <www.dipmat.unipg.it/~mamone/pubb/sems/bigi03.pdf> [9] Connor S., “Glaxo chief: Our drugs do not work on most patients”, The Independent, 8 December 2003. [10] Smith R., “The drugs don’t work”, BMJ, 13 December 2003, vol. 327 <www.bmj.com/cgi/content/full/327/7428/0-h> [11] Abbott A., “More than a cosmetic change”, Nature, 10 November 2005, vol. 438, pp. 144-6. [12] Feynman R.P., “Surely You’re Joking, Mr. Feynman!”, Unwin Paperbacks 1986. [13] Mignini L. E., Khan K. S. , “Methodological quality of systematic reviews of animal studies: a survey of reviews of basic research”, BMC Medical Research Methodology, 13 March 2006, 6:10. <www.biomedcentral.com/1471-2288/6/10> Competing interests: None declared |
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Kathy A Archibald, Director, Europeans for Medical Progress London W13 0YR
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Marco Mamone-Capria's observations are clear and irrefutable - though proponents of animal experimentation will undoubtedly refute them! The waters of this debate have become muddied by the sheer volume of publications making the implicit assumption that the animal experiments involved in any particular field of research were predictive and were therefore responsible for guiding the direction of that research. But it is probably more often the case that clinical observation drives the direction of research, for which 'validatory' animal experimentation is often then awarded the credit. A good illustration of this is provided by BMJ's Medical Milestones supplement, celebrating key advances since 1840s. All 15 stories were an enthralling read, with many important take-home messages. One lasting impression left on me was how they were driven by the ability of the human mind to harness both serendipitous and diligently-sought discoveries to the purpose of solving human health problems, as perceived through careful observation of patterns of disease and individual responses to disease. The key observations and discoveries were necessarily clinical in nature. Yet we are constantly told that 'virtually every medical breakthrough has relied upon animal experimentation, without which medical progress would cease.' In light of these 15 stories, that claim rings very hollow. Of course, animal experimentation has been involved in much medical progress - but has it been the driver of that progress and would future progress be impossible without it? Of course not. 250 MPs and 83% of GPs in a nationwide survey (see www.curedisease.net) want to see an independent scientific evaluation of the clinical relevance of animal experimentation. Yet the Government prefers the advice of those campaigning to prevent an evaluation which would be in all our interests. As the champions of evidence based medicine as a Medical Milestone point out: the results of evidence based medicine often clash with the agenda of special interest groups. Competing interests: Director of Europeans for Medical Progress: an independent organisation devoted to rigorous scientific analysis of animal experimentation to assess the balance of help or harm to human health: www.curedisease.net |
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Marlene A. Thompson, Housewife NG15 6DN
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Marco Mamone-Capria is right to question the relevance of animal experiments to human health, and so is K. Archibald that it is clincal research in humans that advances medical progress. Lawrence Altman MD, medical correspondent to the new York Times, spent 30 years researching medical discoveries and his book 'Who Goes First' writes; "Whenever a doctor discovers a new drug, treatment or therapy, or tries to unravel a mystery of physiology or disease, human experimentation is necessary. Even after thousands of animal experiments our biologic uniqueness requires human expermentation". Many other researchers are aware of the fallacies of animal experiments but reluctant to denounce them for fear of jeopardising careers of funding source. The bulk of research is funded by the pharmaceutical industry which must produce a continual flow of new drugs in order to survive. 'Alternative' methods of research are ignored as this would limit the number of products reaching the market, thereby affecting profits, the ultimate goal of research today. Considering the increasing use of animals in research shouldn't we be seeing an improvement in health? In fact the opposite is true. Years of experiments on billions of animals has not produced a single cure, nor stemmed the huge increase in diseases. In fact we have we have more sickness and disease today than at any time in history and drug related diseases have reached epidemic proportions. The statistics speak for themselves. Competing interests: None declared |
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Timothy I. Musch, Professor Department of Anatomy & Physiology, College of Vet Med, Kansas State University, Manhattan, KS 66506, Robert G. Carroll, Armin Just, Pascale H. Lane, and William Talman
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Editor—The Perel et al. study, “Comparison of treatment effects between animal experiments and clinical trials: systematic review,” is narrow in both size and scope.1 It examines only six examples of one particular aspect of animal research. The authors themselves noted in the conclusion of the original version of this paper published on the University of Birmingham website that their sample size “was far too small to give precise statistical estimates of the extent of concordance” between human and animal studies.2 Unfortunately, small sample size was not the only constraining factor of this study. The authors were also limited by their narrow view of animal research. This paper only examined immediate preclinical testing of new drug therapies, but animal research aids medical science in many more ways. In addition to these tests, animal studies play a role in the initial development of candidate drugs, and the development and testing of medical devices (e.g. pacemakers) and surgical procedures (e.g. heart surgery). Even more vital, animal research informs clinical research by building the foundation of biological knowledge. Basic research that expands our understanding of how life systems function indicates to clinicians not only what direction to pursue but what directions are possible. Although animal research informs clinical research, its circumstances and experimental goals differ from those of clinical research. Thus their protocols and experimental designs necessarily differ. Animal studies generally seek a mechanism of action for treatment, rather than treatment efficacy. They are usually conducted on defined, genetically homogenous subjects with near perfect compliance, as opposed to the large scale diversity of genetics and behavior of a clinical population. Some clinically necessary procedures, such as double-blinding, serve little purpose in an animal study, since rats are not susceptible to the placebo effect. Furthermore, accepted standards for animal welfare as well as many national and institutional protocols insist that sample sizes of animal studies be small. Despite these differences, the protocol used by Perel et al. to determine that the animal studies were of “poor” quality was based, for the most part, on standards meant for large clinical trials. 1 The authors also claimed in their ‘Methods’ section that they “were unaware of the results of the animal studies when selecting the six interventions.”1 However, the first Basic Principle of the World Medical Association Declaration of Helsinki states that clinical research “should be based on adequately performed laboratory and animal experimentation.”3 This means that for any clinical study, one may reasonably assume that animal studies showed a positive result. Otherwise, the clinicians would be ethically remiss for placing humans at risk. By only examining animal studies that advanced to human trials, the authors ignore the many other animal studies that stopped known hazards from being tested in humans. Animal research may not be a perfect predictor of clinical results, but it is much better than going directly to human trials without any preliminary screening. Just as computer simulations and cell cultures reduce the number of animal studies that are necessary, animal studies hone the list of therapeutic possibilities further to a selection of reasonably safe expectations for clinical research. Will the authors next examine via systematic review the concordance of cell culture studies to clinical trials? Timothy I. Musch, PhD Robert G. Carroll, PhD Armin Just, MD PhD Pascale H. Lane, MD William T. Talman, MD References 1. Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ, 2006; doi: 10.1136/bmj.39048.407928.BE (published 15 December 2006) ‹http://www.bmj.com/cgi/rapidpdf/bmj.39048.407928.BEv1› 2. Perel P, Roberts I, Sena E, Wheble P, Sandercock P, Mcleod M, Mignini L et al. Testing treatment on animals: relevance to humans. University of Birmingham Department of Public Health and Epidemiology Website. 2006 ‹http://www.pcpoh.bham.ac.uk/publichealth/nccrm/PDFs%20and%20documents/Publications/JH18_Final_Report_May_2006.pdf› 3. World Medical Association Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects. U.S. Food and Drug Administration Website. 1989 ‹http://www.fda.gov/oc/health/helsinki89.html› Competing interests: None declared |
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Janusz A Jankowski, Professor in GI Oncology Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary, Oxford, OX2 6HE., Lea-Anne Harrison and Janusz Jankowski.
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We read with great interest the article by Perel et al. This article is timely as it highlights the unsatisfactory surrogate of many animal model systems for human disease. One particular area of medicine where human research has needed models is for Barrett’s oesophagus, which is perhaps the Western world’s commonest premalignant lesion 1. Unfortunately the clinical evidence to assess the value of therapeutic interventions like acid suppression takes many years 10 or more in large multi-million trials like the ASPirin Esomeprazole Chemoprevention Trial (AspECT) 2. Several animal models, especially rodents 3, 4, and even the dog 5, 6, are frequently used. The trouble with these models is that the rodent foregut is different from that in man. Furthermore some of these models give rise to lesions that don’t recapitulate human precursors or histological malignant lesions. These lesions often don’t even exhibit the same genetic alterations in man and even between sub-species show great variability. In addition the surgical rerouting of acid and bile causes simultaneous alterations in hypoxic injury, inflammation, bacterial colonisation not to mention unphysiological biochemistry. Moreover most models also rely on the use of potent carcinogens that further perturb stem cell adaptive responses. It is therefore important that animal models of human disease should be characterised and graded according to their relevance across a spectrum of parameters such as physiological, pathophysiological and genetic determinants. 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. References: 1. Devesa SS, Blot WJ, Fraumeni JF, Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998;83(10):2049-53. 2. Jankowski JA, Moayyedi P. Aspirin as chemoprevention for Barrett's esophagus: a large RCT underway in the UK (original research correspondence). J Natl Cancer Inst 2004;96:885-7. 3. Pera, M., Brito, M. J., Poulsom, R., Riera, E., Grande, L., Hanby, A., and Wright, N. A. (2000) Duodenal-content reflux esophagitis induces the development of glandular metaplasia and adenosquamous carcinoma in rats. Carcinogenesis 21, 1587-1591. 4. Su, Y., Chen, X., Klein, M., Fang, M., Wang, S., Yang, C. S., and Goyal, R. K. (2004) Phenotype of columnar-lined esophagus in rats with esophagogastroduodenal anastomosis: similarity to human Barrett's esophagus. Lab Invest 84, 753-765. 5. Bremner, C. G., Lynch, V. P., and Ellis, F. H., Jr. (1970) Barrett's esophagus: congenital or acquired? An experimental study of esophageal mucosal regeneration in the dog. Surgery 68, 209-216. 6. Kawaura, Y., Tatsuzawa, Y., Wakabayashi, T., Ikeda, N., Matsuda, M., and Nishihara, S. (2001) Immunohistochemical study of p53, c-erbB-2, and PCNA in barrett's esophagus with dysplasia and adenocarcinoma arising from experimental acid or alkaline reflux model. J Gastroenterol 36, 595- 600. Competing interests: None declared |
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Neville W Goodman, Consultant Anaesthetist Bristol, BS10 5NB, UK
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Perel et al report that randomisation and blinding were rarely reported in animal experiments. This was our conclusion from a comparison of clinical and laboratory studies in anaesthetic journals (1). Sample size was also smaller (median 6 vs 19), and failure in some aspect of the study protocol was less likely to be reported in laboratory studies than in clinical studies(2 vs 43). It would have been nice to have been cited. 1 Watters MPR, Goodman NW. Comparison of basic methods in clinical studies and in vitro tissue and cell culture studies in three anaesthesia journals. Br J Anaes 1999;82:295-298. Competing interests: Author of a paper on a similar subject that was not cited. |
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