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EDITORIALS: Daniel G Hackam Translating animal research into clinical benefit BMJ 2007; 334: 163-164 [Full text]

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Translational medicine and clinical domain.

Giuseppe Lippi, Gian Cesare Guidi, Mario Plebani   (26 January 2007)

Studies in animals should be more like studies in humans.

Alexander SD Spiers   (28 January 2007)

Moving away from animal research for clinical benefit

Kathy A Archibald   (29 January 2007)

Basic flaw in animal research overlooked

Bina A. Robinson   (31 January 2007)

Criticism of animal research too narrow

Roger Fisken   (6 February 2007)

Flaws With Animal Research a Deep-Rooted Problem

Aysha Z Akhtar, M.D., M.P.H., Jarrod Bailey, Ph.D. Senior Research Consultant   (9 February 2007)

Systematic reviews demonstrate poor clinical utility of animal experimentation

Andrew D Knight   (15 February 2007)

Thoroughly planned animal studies can enhance clinical benefit--animal data are necessary

Dr. Filip Konecny   (14 August 2007)

Translational medicine and clinical domain. 26 January 2007
Giuseppe Lippi, Associate Professor of Clinical Biochemistry Department of Morphological and Biomedical Sciences, Verona University, 37134, Verona, Italy, Gian Cesare Guidi, Mario Plebani Send response to journal: Re: Translational medicine and clinical domain.	We have read with interest the editorial on translation medicine focused on theoretical and methodological flaws that would explain why a minor part of experimental studies on the animal model translate to the clinical domain (1). We agree with this analysis. However, there may be additional scientific, financial, ethical, regulatory and practical hurdles that makes inefficient this process besides methodological biases in animal experimentation and diversity between animal and human pathophysiology (2). Although experimental and clinical research are pursuing the same targets of improving disease understanding and cost-effective decision making, in several occasions they proceed as parallel, rather than coordinated tracks. Therefore, a part of this fail in translation arises from to the lack of an effective audit/feedback between clinicians and researchers that would guide the animal research to more appropriate and efficient goals for the human health. Translational research should be inspired by ongoing efforts in basic and clinical research and not competing with them (2). Then, due to the extensive investments placed in biomedical research, an open and truthful coalition of academia and the drug industry is essential. The industry heavily founds many academic institutions to run animal research and some medical schools might need to make compromises for fear that companies would take the research elsewhere. Consequentially, some drug companies may refuse to turn over results, even though researchers had strongly helped come up with them. The reason is that some agreements signed between academic schools and the drug makers require to keep the data confidential, frequently depending on the outcome. The consequence is that negative results may not be emphasized, nor submitted to medical journals for publication. Few solutions have been prospected so far to close the gap between animal research and clinical practice. However, we deem that translational medicine would require to be strongly reorganized, more clinically driven and supported by funding independent from any potential conflict of interest. References 1.Hackam DG. Translating animal research into clinical benefit. BMJ 2007;334:163. 2.Littman BH, Di Mario L, Plebani M, Marincola FM. What's next in translational medicine? Clin Sci (Lond) 2007;112:217-27. Competing interests: None declared
Studies in animals should be more like studies in humans. 28 January 2007
Alexander SD Spiers, Professor of Medicine (Retired) N/A Send response to journal: Re: Studies in animals should be more like studies in humans.	Dr. Hackman is to be congratulated on his careful critique of drug studies carried out in animals, and also his commentary on the meta- analysis reported by Perel and colleagues (1). The latter study is of limited applicability because only six interventions in six conditions were analysed. Despite this, the demonstration of serious methodological flaws throughout the animal data must cast doubt upon the general reliability of therapeutic studies carried out in animals. As a rule, animal studies are carried out in young, healthy animals. Frequently the animals are genetically homogeneous. In some instances the animals are selected because they suffer from a genetically determined disorder that is to be studied, in others a disorder is induced for the purposes of the study. These animals do not have coexisting diseases. The studies are not blinded. Some studies are carried out by pharmacologists who are undoubtedly skilled but are not clinicians and may not even be medically qualified. It is difficult to envisage a setting more different from that of therapeutic studies in human patients. There is a need to make studies in animals correspond more closely to clinical studies in humans. One obvious difference is that animals do not give informed consent. With few exceptions (2) humans must give their consent before being enrolled in a study, and a Human Subjects Committee must approve the methodology of the study, determining that it is of sufficient power to produce a meaningful result and that the risk:benefit ratio is acceptable. There should be Animal Subject Committees to similarly scrutinise drug trials in animals. The task of such committees would be to assess sample size, randomisation of treatments, blinding of observers, selection of animal subjects, statistical methods and elimination of biases that may be introduced by the pharmaceutical company that sponsors the work. As an example of sponsor bias, I was once asked to comment on a commercially sponsored drug study. The scale for reporting the results in individual animals was: Cure, Major Improvement, Moderate Improvement, Some Improvement and No Response. Such a scoring system inevitably biases the results toward improvement! My suggestion that the scoring system should be expanded to include Progressive Disease, Major Adverse Effects and Drug Death was not well received. Researchers and medical journals have waged a - largely successful - campaign that the publication of therapeutic studies in patients should be divorced from the wishes of the sponsoring companies. Surely it is time to insist on the same academic freedom for drug studies in animals. 1)Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 2007;334:197-200. 2)Shakur H, Roberts I, Barnetson L, Coats T. Clinical trials in emergency situations. BMJ 2007;334:165-6. Competing interests: None declared
Moving away from animal research for clinical benefit 29 January 2007
Kathy A Archibald, Director, Europeans for Medical Progress London W13 0YR Send response to journal: Re: Moving away from animal research for clinical benefit	Congratulations, BMJ, on three excellent articles on the thorny issue of the clinical value of animal testing. Pablo Perel et al conclude that "discordance between animal and human studies may be due to bias or to the failure of animal models to mimic clinical disease adequately" (1), while Daniel Hackam concludes that "it seems prudent to be critical and cautious about the applicability of animal data to the clinical domain" (2). Geoff Watts' article (3) on the other hand comes from an animal welfare perspective, though he highlights the view of drug companies and contract research organisations that “the value of the animal data they collected was limited”, or even “of no practical use.” It is becoming increasingly clear that addressing the failings of animal models in the clinical domain entails shifting the emphasis away from animal studies, to more promising methods such as microdosing. Simon Festing of the Research Defence Society effectively says as much, with his comment that such methods have been developed for scientific reasons (3). But there is no evidence to support the contention that "You could phase out the use of animals if you were prepared to put more risk on to humans". The evidence suggests that employing a battery of human-based tests, including microdosing, for assessing the safety of new drugs would decrease the risk to humans currently posed by our reliance on 'proof of safety in animals.' Think of TGN1412, or this example from the Perel study (1): corticosteroids were administered to head injury victims for decades, based on evidence of benefit from animal tests. This misguided practice is estimated to have killed 10,000 patients.[4] 1) Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 2007;334:197-200. 2) Hackam DG. Translating animal research into clinical benefit. BMJ 2007;334:163. 3) Watts G. Alternatives to animal experimentation. BMJ 2007;334:182 -184 4) Daily Telegraph. 8 October 2004. Head injury drugs 'may have killed 10,000'. By David Derbyshire, Science Correspondent Competing interests: 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
Basic flaw in animal research overlooked 31 January 2007
Bina A. Robinson, editor Swain, NY 14884, USA Send response to journal: Re: Basic flaw in animal research overlooked	This study provides some valuable insights into why animal research seldom applies to humans. Like so many other studies trying to ascertain why animal research so often fails, this study fails to identify the real reason: namely that there are so many differences between species on so many levels that results obtained one species apply to another only in cases of random coincidence. Instead of tackling the Herculean task of trying to sort out these differences, it would be a lot simpler and more practical to dump archaic animal experimentation in favor of the multiple non-invasive nethods that are already available. Besides inertia, I suggest the reason we are stuck in the rut of trying to ascertain human reactions from other species is that too many people and institutions are making money from it. Competing interests: Director of Civitas: Citizens for Planetary Health
Criticism of animal research too narrow 6 February 2007
Roger Fisken, Consultant Physician Friarage Hospital, Northallerton, North Yorkshire, UK,, DL6 1JG Send response to journal: Re: Criticism of animal research too narrow	Once again the BMJ manages to outdo the lay press in using an irresponsible headline ("Animal testing: is it worth it?") to front a much less dramatic story. The study by Perel et al (1)looked at six therapeutic interventions and did a valuable job in exposing serious shortcomings in many of these studies. But animal research covers thousands of different types of work, from molecular genetics to immunity to electrophysiology, as well as pharmacology and therapeutics. It makes no sense to cast a slight on all animal experimentation because of problems in one particular area. It is also depressing to see the old canard being hauled out yet again, to the effect that animals are so different from humans that drug trials on them are inapplicable to human disease. Anyone who opens a book of veterinary pharmacology and therapeutics will see immediately that almost all of the drugs used by veterinary surgeons are identical to those used to treat comparable human diseases. 1) Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 2007;334:197-200. Competing interests: I have conducted basic (non-pharmaceutical) research on animals in the 1970s
Flaws With Animal Research a Deep-Rooted Problem 9 February 2007
Aysha Z Akhtar, M.D., M.P.H., Senior Medical and Research Advisor PCRM 5100 Wisconsin Ave. NW, Suite 400, Washington DC, 20016, USA, Jarrod Bailey, Ph.D. Senior Research Consultant Send response to journal: Re: Flaws With Animal Research a Deep-Rooted Problem	Editor(s): Kudos to you for encouraging discussion and debate regarding animal experimentation.(1) We agree with Hackam’s editorial that methodological flaws constitute a prevalent problem among animal studies, but believe there is a more inherent and confounding problem: inter-species differences in physiology. The more we study the relevance of animal tests, the more apparent their shortcomings become. Even subtle physiological differences between humans and animals can manifest as profound differences in disease physiology and treatment effectiveness and safety. For example, numerous differences in spinal cord physiology and reaction to injury exist between species and even strains within a species.(2-4) These differences likely contribute to the repeated failure of spinal cord treatments that have tested safe and effective in animals to translate into human benefit. Here are just a few of the myriad examples: numerous beneficial agents for stroke, cancer, and AIDS in animals have failed to translate into effective clinical therapies; tests in rodents for predicting human carcinogenicity with a false negative rate approaching two-thirds,(5) potentially causing widespread human exposure to carcinogens;(6) teratology studies in animals that concur with human studies at best half of the time;(7) and the Vioxx (killing over 140,000 people (8-10)) and TGN1412 disasters (severely injuring six clinical trial patients), both of which failed to show adverse reactions in animal tests. A major shift in our research paradigm is long overdue. The move away from animal experiments toward more accurate methods of studying disease and intervention is scientifically superior and more ethical for humanity, as well as for animals. 1. Hackam DG: Translating animal research into clinical benefit. BMJ 2007; 334: 163-164. 2. Ma M, Wei P, Wei T, Ransohoff RM, Jakeman LB: Enhanced axonal growth into a spinal cord contusion injury site in a strain of mouse (129X1/SvJ) with a diminished inflammatory response. J Comp Neurol 2004; 474:469-486. 3. Popovich PG, Wei P, Stokes BT: Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J Comp Neurol 1997; 377:443-464. 4. Schmitt C, Miranpuri GS, Dhodda VK, Isaacson J, Vemuganti R, Resnick DK: Changes in spinal cord injury-induced gene expression in rat are strain-dependent. The Spine Journal 2006; 6:113-119. 5. Lave LB, Ennever FK, Rosenkranz HS, Omenn GS: Information value of the rodent bioassay. Nature 1988; 336:631-633. 6. Ennever FK, Lave LB: Implications of the lack of accuracy of the lifetime rodent bioassay for predicting human carcinogenicity. Regulatory Toxicology and Pharmacology 2003; 38:52-57. 7. Bailey J, Knight A, Balcombe J: The future of teratology research is in vitro. Biogenic Amines 2005; 19:97-145 8. Topol EJ: Failing the public health – rofecoxib, Merck, and the FDA. NEJM 2004;351:1707-9. 9. Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA: Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365:475-81. 10. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam M, Baron JA, for the Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. NEJM 2005;352:1092-1102. Competing interests: Senior Research Advisor and Consultant for Physicians Committee for Responsible Medicine, a non-profit organization dedicated to the promotion of alternatives to animal research.
Systematic reviews demonstrate poor clinical utility of animal experimentation 15 February 2007
Andrew D Knight, Director Animal Consultants International, 91 Vanbrugh Ct., Wincott St., London SE11 4NR, UK Send response to journal: Re: Systematic reviews demonstrate poor clinical utility of animal experimentation	Since animal experimentation first began, advocates have claimed they are crucially important to the development of cures for human diseases. No matter how eminent such advocates and how earnest such claims, such opinions do not constitute an adequate form of evidence, however, given the contrary opinions of other scientists and the widespread social concern about animal experimentation. The need for firm evidence of the clinical utility or lack thereof of relatively expensive animal experimentation is also becoming ever more urgent given increasing competition for scarce research funding. Accordingly, systematic reviews of the clinical utility of animal experiments are warranted. One of the first such reviews was published in 2005 by Lindl et al. [1]. After examining citations of all published animal experiments conducted at three German universities between 1991 and 1993, Lindl et al. located only four publications indicating a direct connection with human outcomes. In each of these cases, however, the human outcomes were opposite to those obtained in animals. In 2005 my colleagues and I published an examination of the concordance between various animal species and humans for 1,396 putative teratogens [2]. We found a huge variability in positive predictability for known human teratogens, the mean of which was only 51%—hardly better than tossing a coin—with some commonly utilised species showing a high rate of false negative results. In 2006 we demonstrated the limited utility of animal carcinogenicity data in deriving human risk assessments [3-4]. We found that for environmental contaminants of greatest US concern, the Environmental Protection Agency (EPA)—the US federal agency most responsible for protecting public health from environmental contaminants—considers animal data useful for predicting human carcinogenicity less than half (41.9%) the time. Furthermore, highly significant (p<0.0001) differences of human carcinogenicity classifications of identical chemicals between different agencies demonstrated that the EPA nevertheless remains over- reliant on animal carcinogenicity data, that it consequently tends to over -predict carcinogenic risk, and that the true human predictivity of animal carcinogenicity data is even poorer than indicated by EPA figures alone. EPA policy erroneously assuming that tumours in animals are necessarily indicative of human carcinogenicity was implicated as a primary cause of these errors. Chimpanzees are the species most closely related to humans, and consequently, most likely to be predictive of human outcomes when used in biomedical research. However, in 2006 I demonstrated that of 95 chimpanzee experiments randomly selected from a population of 749 published during a recent decade, only 14.7% (14/95) were cited by 27 papers that appeared to describe well developed methods for combating human diseases [5]. However, detailed examination of these medical papers failed to yield any chimpanzee study able to demonstrate an essential contribution, or, in most cases, a significant contribution of any kind, towards the development of the medical method described. In 2006 Hackam & Redelmeier published a systematic review examining the frequency with which highly cited animal studies translated into successful human research [6]. Of 76 animal studies with a median citation count of 889 (range: 639-2,233), only 36.8% (28/76) were replicated in human randomized trials. 18.4% (14/76) were contradicted by randomized trials, and 44.7% (34/76) had not been tested. These systematic reviews clearly do not support the opinions of advocates that animal experiments are beneficial in the development of human therapeutic interventions and the assessment of human toxicity. On the contrary, they consistently demonstrate that animal experiments are of low clinical utility. In fact, no systematic review has been published in a peer-reviewed biomedical journal demonstrating that animal experiments are as beneficial in combating human diseases as advocates frequently claim. To persist with such claims contrary to this consistent and growing body of evidence is unscientific. Differences between laboratory animals and humans that may contribute to their poor clinical utility include differing susceptibility to, aetiology and progression of diseases; differing absorption, tissue distribution, metabolism, and excretion of chemotherapeutic agents; and differences in the toxicity and efficacy of pharmaceuticals [7]. The results are that laboratory animals are unreliably predictive of human outcomes, and that experiments on them constitute an inefficient means of combating human diseases. The poor methodological quality of many animal experiments also contributes to their lack of clinical utility. This has also been demonstrated in several systematic reviews. In 2001 Horn et al. reviewed 20 animal studies examining the efficacy of Nimodipine in animal models of focal cerebral ischemia [8]. Although animal studies are intended to be conducted prior to human trials to allow detection of potential toxicity and assessment of efficacy, in this case clinical trials proceeded concurrently with animal studies, which demonstrated equivocal evidence of efficacy. In 2001 Roberts et al. systematically reviewed 44 randomised controlled animal studies examining the efficacy of fluid resuscitation in uncontrolled haemorrhage [9]. They found that poor sample size choices left most studies underpowered, limiting the conclusions that could be derived, and that little information was provided on possible biases in the selection of treatment groups. In 2004 Pound et al. reviewed six systematic reviews examining the extent to which animal experiments had informed human clinical research, and found that in two cases clinical trials were conducted concurrently with animal studies, in three cases clinical trials were conducted despite evidence of harm from prior animal studies, and in the remaining case the outcome of the animal study contradicted the findings of previous investigators, who appeared to have cited only studies that supported their prior views [10]. In 2006 O’Collins et al. examined 1,026 experimental treatments in acute stroke, finding that 114 drugs used clinically were no more effective in animal experiments than 912 drugs tested only in animals [11]. Accordingly, they questioned whether the most efficacious drugs are, in fact, being selected for clinical trials. They called for greater rigor in the conduct, reporting, and analysis of animal data. The 2006 systematic review of highly cited animal studies by Hackam & Redelmeier found that only 37 (49%) were of good methodological quality. Few studies included random allocation of animals, adjustment for multiple hypothesis testing, or blinded assessment of outcomes [6]. The 2007 review by Perel et al. recently published in BMJ provides the latest addition to this growing evidence base [12]. Upon examining interventions with unambiguous evidence of a treatment effect (benefit or harm) in clinical trials of corticosteroidal treatment for head injury, antifibrinolytics in haemorrhage, thrombolysis in acute ischaemic stroke, tirilazad in acute ischaemic stroke, antenatal corticosteroids to prevent neonatal respiratory distress syndrome, and bisphosphonates to treat osteoporosis, Perel et al. found that three interventions had similar outcomes in animal models, while three did not. Perel et al. reported that the animal studies varied in methodological quality and sample sizes, that randomisation and blinding were rarely reported and that publication bias was evident. Perel et al. consequently called for the application to animal studies of standards for evidence based reporting similar to those applied to clinical trials. They also called for systematic reviews of animal experimental outcomes prior to progression to clinical trials, facilitating better detection of toxicity and efficacy, thereby potentially improving the safety and efficiency of the drug development process. However, as Perel et al. stated, the discordance between human and animal outcomes is unlikely to result from the poor methodological quality of animal experiments alone. The failure of animal models to adequately represent human disease is another fundamental cause, which in contrast, may be impossible to correct, even in theory. The decisions about whether or not to conduct research on animals must always involve weighing the animal and financial costs against the likely benefits of the research. The animal costs of invasive or harmful procedures are readily apparent. However, in 2004 a review of 80 studies by Balcombe et al. demonstrated that virtually all common laboratory species experience rapid, pronounced, and statistically significant elevations in a range of stress-related physiological responses to common laboratory procedures as well, including handling, blood collection, and gavaging [13]. In 2006 Balcombe further demonstrated in a review of over 100 studies that the small, relatively barren cages in which the vast majority of laboratory rodents spend most of their lives also result in deleterious neuroanatomical, psychological and physiological effects [14]. Such effects not only have profound ethical implications, but are also likely to distort scientific outcomes, through the stressful alteration of a range of physiological parameters, and through increased susceptibility to diseases secondary to stress-mediated immunosuppression. Additionally, the human costs must also be considered, when other research fields or preventative medical strategies conceivably more likely to benefit human health may be deprived of funding consumed by relatively expensive animal research. Given these profound bioethical and financial costs, and the widespread and legitimate public concern about animal experimentation, the onus is on those who would spend society’s animal and financial resources on these experiments to clearly demonstrate that they are an efficient means of combating human diseases. To date, they have not done so. Andrew Knight BSc., BVMS, CertAW, MRCVS Director, Animal Consultants International: an internationally-based organisation providing policy expertise on animal issues. REFERENCES 1. Lindl T., Völkel M. & Kolar R. [Animal experiments in biomedical research. An evaluation of the clinical relevance of approved animal experimental projects: no evident implementation in human medicine within 10 years]. [German]. ALTEX 2005;22(3):143-51. 2. Bailey J, Knight A, Balcombe J. The future of teratology research is in vitro. Biogenic Amines 2005;19(2):97–145. 3. Knight A, Bailey J, Balcombe J. Which drugs cause cancer? Animal tests yield misleading results. British Medical Journal USA Oct. 2005;331:E389-91. 4. Knight A, Bailey J, Balcombe J. Animal carcinogenicity studies: 1 poor human predictivity. Alternatives to Laboratory Animals 2006; 34(1):19 -27. 5. Knight A, Bailey J, Balcombe J. Chimpanzee research: 2. lack of efficacy in combating human disease. Altex: Alternatives to Animal Experimentation 2006; 23(2):108. 6. Hackam & Redelmeier. Translation of research evidence from animals to humans. JAMA 2006;296(14):1731-2. 7. Bailey J. Non-human primates in medical research and drug development: a critical review. Biogenic Amines 2005;19(4-6):235–55. 8. Horn J., de Haan R.J., Vermeulen M., Luiten P.G. & Limburg M. Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke 2001;32(10):2433-8. 9. 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 2002;324:474-6. 10. Pound P., Ebrahim S., Sandercock P., Bracken M. & Roberts I. Where is the evidence that animal research benefits humans? British Medical Journal 2004;328:514-7. 11. O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp Bart H & Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol 2006;59:467–77. 12. Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, Mignini LE, Jayaram P, Khan KS. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 2007;334:197- 13. Balcombe J, Barnard N, Sandusky C. Laboratory routines cause animal stress. Contemporary Topics in Laboratory Animal Science 2004;43(6):42-51. 14. Balcombe J. Laboratory environments and rodents' behavioural needs: a review. Laboratory Animals 2006;40(3):217-35. Competing interests: None declared
Thoroughly planned animal studies can enhance clinical benefit--animal data are necessary 14 August 2007
Dr. Filip Konecny, PDF TMDT, TGH Canada M5G 1L7 Send response to journal: Re: Thoroughly planned animal studies can enhance clinical benefit--animal data are necessary	The central principle of pre-clinical animal testing is that the experimental agent must possess biological activity in the animal in order to provide consequential data on both safety and activity endpoints. Poor planning, understanding and partially undermining the value of animal studies lead to poor translation of the animal experimentation into clinical benefit and may lead to public mistrust. The question becomes more complex, when translated results show or depict new phenomena specific for the tested animal with no apparent generalization into human population. If this happens once, data are published with optimism and typically in journal with veterinary problems. When second time comes around, and instead of a universal answer being obtained, the model is usually abandoned. The question then becomes: is it the availability of the animals that experiments are carried out on, without any conditions that has to be set in place before the experiment begins and then carefully re-examined (design, methodology), or it is the non-perception (untrained, lay person) on the part of the experimenter? Almost certainly both cases are similarly relevant, and when they are going hand in hand, results might be disastrous (animal overused by untrained observer). Moreover, it has to be stated that there is not an animal model specific to any human disease-condition, thus, for example, rats cannot be justified to test myocardial infarct, rabbits to test lung emphysema, or mice to investigate breast cancer, etc. As described in the first paragraph, it is not simple to test a variety of treatments on animals such as rodents and then translate the results into primates or humans. Rodents as a mammal group are overused, and while tested, only some information can be deduced. They are physiologically distant from primates; as per their way of life e.g. (nocturnal, multiparous, coprophagic, etc.), thus the question asked (nutrition, hormonal cycle) may never be fully experimentally translated. The response why we overuse rodents as a particular mammal group becomes rational when we are able to find newborns every 3-4 weeks with at least 2-15 offspring. Furthermore, rodents are easy to house, treat, and take care of while in experiments. As for this useful design we may not only skew data, but select an unsuitable model for further generalization. Why then are the results of mammal studies not replicated clinically? Several possible explanations exist, with other important facts that may change its perspective. While the replication is not in many cases achievable; toxicology and other studies might at the same time deter or fully stop the clinical application, which indirectly helps to protect human patients. In many cases when mammals are used they are free of comorbidities, often young animals are selected, and usually non-diseased animals are chosen to carry out the experiment, with only limited other tests and competing interventions that humans frequently receive. Thus it is not surprising that finding of methodological biases in animal experimentation, the lack of uniform requirements for reporting animal data compounding this dilemma. In addition, if we closely look at the amount of samples we are taking from humans while in experiments and how much scrutiny we put on that examination, we have to ask why we do not collect such amount of data and observe each animal while in experiments with the same scrutiny? As a partial argument can be stated that it is not an easy task to examine animals without proper skills, qualifications or experience. This issue, however, can be addressed early on in the methodology, by examination by trained veterinarian. Moreover, this could be regarded as a benefit for the whole study, if physiological alterations can be rapidly recognized and documented. Therefore only trained personnel, preferably with clinical skills, should be allowed to perform animal studies; argumentatively and comparably to trained nurses that collect data from humans. In addition, if the results are to be reported they should be discussed with a veterinarian prior to selection of overly optimistic animal biased data without paying attention to equally valid negative result. The importance of pre-clinical animal studies is enormous, the impact however lies in the careful and meticulous planning in order to avert possible public mistrust or doubts. When studies are carried out only trained personnel has to be involved. When results are presented they should be discussed prior to submission with a veterinarian experienced in research. Competing interests: None declared