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Animal Studies Bibliography

This component of the project was conducted before the framework described in this document was fully developed and finalized. A preliminary framework was used into which the various articles were mapped. This mapping was done in the form of bolded codes that appear at the end of each article description, and correspond to the following dimensions.

I. Annotated Articles

1. ’t Hart BA, Amor S, Jonker M. Evaluating the validity of animal models for research into therapies for immune-based disorders. Drug Discov Today. 2004;9:517–24. [PubMed: 15183159]

This article examines monoclonal antibody trials for immunotherapy in transplantation and for chronic diseases (rheumatoid arthritis and MS), and assesses the validity and predictive strength of animal models currently used for the development of effective therapies. The vast majority of immunology drugs have been preclinically tested in rodents, and, given the immunological differences between these mice and humans, it is not surprising that many fail to prove efficacious in humans. The authors argue that the outbred nature and immunological proximity of nonhuman primates to humans offer unique disease models to test whether the therapeutic principle holds in a higher species. [1c, 2a, 3b]

2. Alonso de Lecinana M, Diez-Tejedor E, Carceller F, Roda JM. Cerebral ischemia: from animal studies to clinical practice. Should the methods be reviewed? Cerebrovasc Dis. 2001;11 Suppl 1:20–30. [PubMed: 11244197]

This article examines a number of preclinical focal cerebral ischemia models and discusses the reasons why findings from this research often fail to translate into clinically effective strategies. They present a number of explanations, including: the homogeneity obtained in animal models versus the high level of variability demonstrated among humans for critical pathological parameters of the condition; different PK properties; inattention to side effects and drug interactions in animal models; and methodological discrepancies, such as use of female, young animals and the use of endpoints that do not mirror clinical endpoints. The authors argue that these discrepancies must not invalidate preclinical studies. Rather, the knowledge of these reasons can help to optimize experimental models so that they become comparable with the clinical situation. [1b, 2a, 3a]

3. Anderson LM. Environmental genotoxicants/carcinogens and childhood cancer: bridgeable gaps in scientific knowledge. Mutat Res. 2006;608:136–56. [PubMed: 16829162]

This article explores why, in numerous epidemiological studies, associations between childhood cancers and exposure to genotoxicants, including tobacco smoke, have been weak and hard to reproduce. The authors describe numerous scientific knowledge gaps and argue that conventional animal models should have a place in developing mechanistic understanding in filling these gaps. Perinatal bioassays in animals of specific environmental candidates, for example, benzene, could help guide epidemiology. Genetically engineered animal models could be useful for identification of chemical effects on specific genes. [1b, 2a, 3a, 3b]

4. Ayhan Y, Sawa A, Ross CA, et al. Animal models of gene-environment interactions in schizophrenia. Behav Brain Res. 2009;204:274–81. [PMC free article: PMC2735613] [PubMed: 19379776]

5. Bailey GP, Marien D. What have we learned from pre-clinical juvenile toxicity studies? Reprod Toxicol. 2009;28:226–9. [PubMed: 19446432]

This article assesses the scientific value of preclinical juvenile toxicity studies that are conducted to better predict the safety of pediatric drugs. The authors reviewed data from 10 pharmaceutical companies covering 39 studies. The authors found that only in 20 percent of the studies was it felt that the pre-clinical work contributed to the pediatric clinical trials and the preclinical studies were considered to have contributed to the product label in approximately 30 percent of cases. The authors raise questions about the need for clear scientific rationales in conducting these studies, suggesting that recently-implemented regulatory policies may be encouraging unnecessary and/or uninformative studies. [1c, 6]

6. Baker DH. Animal models in nutrition research. J Nutr. 2008;138:391–6. [PubMed: 18203909]

This article reviews how experimental animal studies have contributed basic nutritional information concerning bioavailability of nutrients and nutrient precursors. It describes advantages, disadvantages and idiosyncrasies of numerous models, but does not offer a critical examination of them. [1c, 3a]

7. Bath PM, Macleod MR, Green AR. Emulating multicentre clinical stroke trials: a new paradigm for studying novel interventions in experimental models of stroke. Int J Stroke. 2009;4:471–9. [PubMed: 19930059]

Building on the meta-analyses of neuroprotective agents in stroke led by Macleod, the authors argue for a fundamental paradigm shift away from performing preclinical studies in individual laboratories to performing them in an organized group of independent laboratories run by a steering committee and supported by a coordinating center, external data monitoring committee and outcome adjudication committee. This structure mimics the practice of multicenter RCTs. [1a, 2a]

8. Belser JA, Szretter KJ, Katz JM, et al. Use of animal models to understand the pandemic potential of highly pathogenic avian influenza viruses. Adv Virus Res. 2009;73:55–97. [PubMed: 19695381]

This article reviews the advances made toward understanding the molecular determinants of avian influenza viruses. The use of mouse and ferret models has provided new insights into the contribution of virus and host responses and transmissibility, and in identifying the role of individual viral gene products and mapping the molecular determinants that influence the severity of disease. The article discusses the suitability of various animal models for their ability to reproduce human symptoms and pathogenesis (see Figure 1 in article). Authors argue that understanding the mechanisms of virulence of avian influenza viruses is crucial not only to develop improved antivirals and vaccines but also as a means to estimate the likely severity of disease for a given pandemic strain. [1c, 2a]

9. Benatar M. Lost in translation: treatment trials in the SOD1 mouse and in human ALS. Neurobiol Dis. 2007;26:1–13. [PubMed: 17300945]

This article reports a meta-analysis of ALS treatment trials in mouse models and explores possible reasons for failure to translate promising preclinical findings into effective human treatments. While examining a number of reasons related to the methodological quality of these animal studies, the author also considers the relevance of the mouse model to human ALS, suggesting that the genetic mutation and time of treatment initiation used in most experiments are not relevant for the type of ALS (sporadic vs. familial) that the results are used to advance to human trials. [1a, 2a, 3a]

10. Bergman KL. The animal rule and emerging infections: the role of clinical pharmacology in determining an effective dose. Clin Pharmacol Ther. 2009;86:328–31. [PubMed: 19571806]

This article examines drug development for emerging infections in translational pharmacology. Given the nature of emerging and re-emerging infections, specifically their severity (often life-threatening), the low incidence of natural occurrence even in endemic areas, and the potential of the infective agent to develop altered virulence and resistance to drugs, traditional drug development pathways (discovery, preclinical development, clinical development, post-approval) may not be possible. The Animal Rule — which allows the FDA to grant marketing approval based solely on animal studies if those studies are seen as providing substantial evidence of effectiveness in humans—is particularly relevant for the purposes of this report. Criteria for use of the Rule include: reasonably well-understood pathophysiological mechanism of toxicity; effects demonstrated in more than one animal species; end point clearly related to the desired benefit in humans, data or information on the pharmacokinetic/pharmacodynamics (PK/PD) of the product or other relevant data or information, in animals and humans, to allow selection of an effective dose in humans. [1c, 2a, 3a, 6]

11. Bodewes R, Rimmelzwaan GF, Osterhaus AD. Animal models for the preclinical evaluation of candidate influenza vaccines. Expert Rev Vaccines. 2010;9:59–72. [PubMed: 20021306]

This article covers similar terrain as Belser et al (2009), number 8 in this appendix. Table 3 in the article, compares the advantages and disadvantages of various animal models most commonly used in the evaluation of candidate vaccines. It is informative in terms of the important predictive attributes of animal models viz. translation. [1c, 2a, 3a]

12. Bolton C. The translation of drug efficacy from in vivo models to human disease with special reference to experimental autoimmune encephalomyelitis and multiple sclerosis. Inflammopharmacology. 2007;15:183–7. [PubMed: 17943249]

Similar to Friese et al. (2006, number 29 in this appendix), this article assesses preclinical models of experimental allergic (autoimmune) encephalomyelitis (EAE) and multiple sclerosis (MS), and provides some guidance that may improve clinical translation. The authors advocate for EAE models with representative and reproducible features, a uniform scoring system of disease, the inclusion of adequate controls, and careful choice of vehicle and an appreciation of the dose, route and frequency of treatment. They contend that the development of an accepted set of characteristics would provide a true picture of disease progression that could be used to confirm compound efficacy and ultimately help to counteract the discrepancies in drug activity between models and the corresponding human disease. [1a]

13. Bonjour JP, Ammann P, Rizzoli R. Importance of preclinical studies in the development of drugs for treatment of osteoporosis: a review related to the 1998 WHO guidelines. Osteoporos Int. 1999;9:379–93. [PubMed: 10550456]

This article provides an overview of the World Health Organization osteoporosis guidelines, which underline the importance of a preclinical/clinical complementary program to assess the efficacy of new antiosteoporotic drugs. Preclinical studies carried out in the most reliable animal models (i.e., the most predictive with respect to human calcium and bone metabolism and drug responsiveness) are aimed at testing drug efficacy on bone mass/mineral density, microarchitecture and mechanical resistance in well-controlled conditions. The authors’ review of animal studies indicated that these preclinical investigations were highly predictive of clinical outcome for most, if not all, drugs tested. The results of animal studies were able to predict whether changes in bone mass and/or bone mineral density were associated with modifications in bone fragility and therefore in fracture rate in osteoporotic patients. Preclinical studies also predicted the tolerance of bone tissue to increasing doses of the drugs, particularly with respect to the processes of modeling, remodeling, matrix mineralization and fracture healing. This is one of very few instances reporting success of preclinical animal models in terms of their ability to predict therapeutic efficacy. [1a, 2a, 3c]

14. Bracken MB. Why animal studies are often poor predictors of human reactions to exposure. J R Soc Med. 2009;102:120–2. [PMC free article: PMC2746847] [PubMed: 19297654]

15. Bracken MB. Why are so many epidemiology associations inflated or wrong? Does poorly conducted animal research suggest implausible hypotheses? Ann Epidemiol. 2009;19:220–4. [PubMed: 19217006]

In these two articles, Bracken suggests that the poor quality of animal research, and the way it is both synthesized and represented (dearth of systematic reviews; publication and outcome reporting biases), underlies the nonreplicability of many epidemiologic observations. [1a, 3a]

16. Chatzigeorgiou A, Halapas A, Kalafatakis K. The use of animal models in the study of diabetes mellitus. In Vivo. 2009;23:245–58. [PubMed: 19414410]

This article provides a largely uncritical review and evaluation of rodent models of Types 1 and 2 diabetes. See Roep et al., 2004 for a more critical assessment of the limitations of rodent models, especially for Type 1 diabetes. [1c]

17. Corry DB, Irvin CG. Promise and pitfalls in animal-based asthma research: building a better mousetrap. Immunol Res. 2006;35:279–94. [PubMed: 17172652]

The article reviews the challenges of animal models in asthma research. Given the complex disease process and heterogeneous pathogenesis of asthma, simple animal models have not reproduced in detail the underlying allergic immune mechanisms responsible for most forms of asthma and asthma-like diseases and correlate them with a limited set of clinically relevant disease variables. The authors suggest a number of technical improvements that could improve the reliability of experiments, but validity concerns (about disease initiation and exacerbation) persist and will only be resolved by continued animal experiments focused on understanding asthma pathophysiology. [1c, 2a, 3a, 3b]

18. Crossley NA, Sena E, Goehler J, et al. Empirical evidence of bias in the design of experimental stroke studies: a metaepidemiologic approach. Stroke. 2008;39:929–34. [PubMed: 18239164]

The authors systematically identified and reanalyzed meta-analyses that described interventions in experimental stroke in order estimate the impact of various study quality items on efficacy estimates. They found that studies that failed to blind investigators and included healthy animals, as opposed to animals with comorbidities, overstated effect sizes. These findings are in keeping with this research group’s other results concerning study quality in the area of stroke. [1a]

19. Dehoux JP, Gianello P. The importance of large animal models in transplantation. Front Biosci. 2007;12:4864–80. [PubMed: 17569616]

The authors review large animal models commonly used to evaluate organ transplant experiments and analyze the robustness of several models of human immune and physiological systems (especially allospecific tolerance and xenotransplantation). They suggest that rodent models be used to discover new genes and new biological pathways by using tools such as transgenic and knock-out animals. Large animal models should be used only to confirm findings; swine models seem to be the most appropriate choice, though nonhuman primate models may also provide relevant data. [1c, 2a, 2c, 3a]

20. DiBernardo AB, Cudkowicz ME. Translating preclinical insights into effective human trials in ALS. Biochim Biophys Acta. 2006;1762:1139–49. [PubMed: 16713196]

This article provides an overview of important features in the discovery, development, and validation of disease-modifying therapies and interventions for ALS. The animal (especially mouse) models for ALS thus far have failed to predict response in humans. The reasons for discordant results between mouse and human trials may relate to inherent differences between the mouse and human disease (comparability of pharmacokinetics, routes of delivery, timing of treatment, relevance of familial disease model to sporadic disease). Despite these failures, authors assert that mouse models remain important tool in pursuing new therapeutic approaches. [3a, 3b]

21. Dirnagl U, Macleod MR. Stroke research at a road block: the streets from adversity should be paved with meta-analysis and good laboratory practice. Br J Pharmacol. 2009;157:1154–6. [PMC free article: PMC2743833] [PubMed: 19664136]

22. Dirnagl U. Bench to bedside: the quest for quality in experimental stroke research. J Cereb Blood Flow Metab. 2006;26:1465–78. [PubMed: 16525413]

While this article is largely focused on the poor quality of preclinical stroke research, the author discusses some critical translational hurdles, including: species differences, inappropriate time windows of treatment, effective drug levels not achievable in humans because of toxicity, use of young animals without comorbidity, failure to model white matter damage and protect axons, incongruent end points, and heterogeneity of stroke subtypes in patients, among others. The article (indirectly) raises questions about important trade-offs between reductionist mechanistic models that may be important for basic, narrow discoveries versus more complex models that may better mirror human disease state. [1a, 3a, 3b]

23. Dixon JA, Spinale FG. Large animal models of heart failure: a critical link in the translation of basic science to clinical practice. Circ Heart Fail. 2009;2:262–71. [PMC free article: PMC2762217] [PubMed: 19808348]

This article provides an overview of a number of animal models and species used preclinical research on heart failure (including recent developments in gene therapy and stem cells), highlighting the utility and value of large animal models. The authors suggest that large animal models have often played a critical role in successful translation from bench to bedside. They caution that recent advances in our understanding heart failure at the molecular and protein levels will not result in successful translation without large animal models that recapitulate the clinical heart failure phenotype in ways that murine models cannot. [1c, 3a]

24. Dragunow M. The adult human brain in preclinical drug development. Nat Rev Drug Discov. 2008;7:659–66. [PubMed: 18617887]

This article takes as its starting point the fact that no effective neuroprotective agent (save tissue plasminogen activator (TPA) has been developed for humans for neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Authors suggest that animal models are necessary for neuroprotective drug development (especially dose selection and toxicological assessment) but are not sufficient. Animal models of human brain disorders by necessity tend to focus on and therefore model specific aspects of the disease, and cannot reproduce the complex array of human neuropathology and symptomatology. They recommend expanding target validation by using human brain tissue microarray screening and direct adult human brain cell testing at an early preclinical stage (an adult human brain preclinical platform) to isolate molecules that protect the human brain (see Figure 2 in article). [2b, 4a]

25. Dyson A, Singer M. Animal models of sepsis: why does preclinical efficacy fail to translate to the clinical setting? Crit Care Med. 2009;37:S30–7. [PubMed: 19104223]

This article takes as a starting point that preclinical models of sepsis (largely utilizing mice and rodents) cannot replicate the complexity of human sepsis. Disparities in severity of insult, species, comorbidities, gender, and age make translation difficult. While the authors do not suggest alternatives to animal models, they argue that the models themselves are too heterogeneous, and recommend using standardized animal models as way of improving translation. [1b, 2a, 3c]

26. Ferrante RJ. Mouse models of Huntington’s disease and methodological considerations for therapeutic trials. Biochim Biophys Acta. 2009;1792:506–20. [PMC free article: PMC2693467] [PubMed: 19362590]

The author of this article reviews some of the successful developments in the use of genetic mouse models of Huntington’s disease, and carefully considers what constitutes sufficient data from mouse models to justify translation to humans. Experiments with these models have yielded many promising therapeutic candidates, but there is a need to prioritize these leads. Given the variability of lab procedures and models, it can be exceedingly difficult to compare evidence of efficacy and effect size. The author offers numerous methodological recommendations that will allow for more rigorous selection of leads for human trials. [1a]

27. Fielden MR, Kolaja KL. The role of early in vivo toxicity testing in drug discovery toxicology. Expert Opin Drug Saf. 2008;7:107–10. [PubMed: 18324874]

This opinion piece focuses on in vivo preclinical toxicity testing and suggests that the predictivity of these models is lacking. The authors recommend larger upfront investment in experiments designed narrowly to obtain a more thorough understanding of the mechanisms of toxicity, arguing that the current experimental paradigm—focused on efficacy and PK properties—does not sufficiently or meaningfully inform the selection and prioritization of compounds. They propose an alternative early testing strategy (Figure 1 in article) that will shift attrition of future failing molecules upstream in the discovery process. [6]

28. Fisher M, Henninger N. Translational research in stroke: taking advances in the pathophysiology and treatment of stroke from the experimental setting to clinical trials. Curr Neurol Neurosci Rep. 2007;7:35–41. [PubMed: 17217852]

This article by one of the developers of the STAIR criteria summarizes some lessons learned from preclinical stroke research to date. Figures 1 (STAIR recommendations) and 2 (lessons learned) within the article’s text provide a useful summary. [1a, 3c]

29. Friese MA, Montalban X, Willcox N, et al. The value of animal models for drug development in multiple sclerosis. Brain. 2006;129:1940–52. [PubMed: 16636022]

The rodent model typically used in preclinical MS studies—induced EAE— does not reproduce all the pathogenetic mechanisms operating in spontaneous human MS. MS is highly heterogeneous in its genetic basis, environmental effects, clinical course, pathological mechanisms, and treatment responsiveness, and this heterogeneity needs to be comprehended and mimicked in any ideal animal model (Box 1 within article). The authors are hopeful that the use of more humanized mouse models (using transgenic and stem cell technologies) that incorporate multiple susceptibility factors may reproduce the clinical heterogeneity of MS better, and improve identification of promising therapeutic approaches. [1a, 3a]

30. Gallegos RP, Nockel PJ, Rivard AL, et al. The current state of in-vivo pre-clinical animal models for heart valve evaluation. J Heart Valve Dis. 2005;14:423–32. [PubMed: 15974538]

This article provides an overview of current animal models of preclinical safety evaluation of prosthetic heart valves developed for use in humans. The authors endorse the use of standard sheep models, which in their estimation most accurately simulates most characteristics of human anatomy and physiology. Of particular relevance to BMEBM is the inclusion of the International Standards Organization guidance in formulating ideal animal studies, summarized in the article in Table 1. [1c, 3b, 6]

31. Ganter B, Giroux CN. Emerging applications of network and pathway analysis in drug discovery and development. Curr Opin Drug Discov Devel. 2008;11:86–94. [PubMed: 18175271]

While not strictly about the predictivity of animal models, this article discusses recent applications of pathway and network analysis for predictive in silico modeling in the area of drug discovery and development. These tools link relevant extracted literature information (including reports of animal experiments) with features that enable analysis and interpretation of the global impact of a disease stage or drug treatment. Such integrated models can link cellular profiles of genomics, proteomic and metabolomic data with the corresponding clinical endpoint, and can provide a new perspective for drug discovery and development. Figure 1 in article describes the workflow embodied in this approach, and includes the role of in vivo preclinical data. [1b, 2a, 2b, 4a]

32. Geerts H. Of mice and men: bridging the translational disconnect in CNS drug discovery. CNS Drugs. 2009;23:915–926. [PubMed: 19845413]

This paper reports on a number of under-appreciated fundamental differences between animal models and human patients in the context of drug discovery with emphasis on Alzheimer's disease and schizophrenia. These differences include the absence of many functional genotypes in animal models and difficulties in simulating the pre-ymptomatic state (Figure 1 in article). The author offers possible solutions to these translational challenges, including organizational improvements (information and cost-sharing collaborations), the better use of negative trial data, technical improvements (development of better imaging biomarkers), the introduction of realistic drug schedules early in drug discovery, and the use of computational models (Figure 2 in article). At bottom, however, the biggest improvements in translation will result from new conceptual models that treat CNS disorders as imbalances of networks rather than mismatches of single targets, and multi-target molecules that may lead to significant clinical improvements. [1a, 3a]

33. Gold R, Linington C, Lassmann H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain. 2006;129:1953–71. [PubMed: 16632554]

This article covers similar terrain as Friese et al. (2006, number 29 in this appendix) and Bolton (2007 number 12 in this appendix) in reviewing EAE models of MS. While acknowledging the limitations of many of the models, the authors argue that they have resulted in many advances of our understanding and treatment of MS, and represent the best hope for further progress in MS treatment. Table 1, which summarizes commonly used rodent models of EAE and their similarities to and differences from human disease, is particularly useful. [1b, 3a, 3b]

34. Gurwitz D, Weizman A. Animal models and human genome diversity: the pitfalls of inbred mice. Drug Discov Today. 2001;6:766–8. [PubMed: 11470580]

This article summarizes the limitations of using inbred mice in preclinical experiments, especially the use of single strains that do not reflect the natural variation of the human patient population. The authors support the development of a mouse genome project that would eventually allow genome-wide comparative genomic studies, leading to the identification of new drug targets that share similar natural variations in mice and humans and, thus, are more suitable for studies in mouse models for human diseases. [1b, 2a]

35. Hackam DG, Redelmeier DA. Translation of research evidence from animals to humans. JAMA. 2006;296:1731–2. [PubMed: 17032985]

36. Hackam DG. Translating animal research into clinical benefit. BMJ. 2007;334:163–4. [PMC free article: PMC1782020] [PubMed: 17255568]

The above two brief papers by Hackam emphasize the poor methodological quality of animal studies. In the systematic review of 76 highly cited animal studies, the authors found that only just over a third translated at the level of human randomized trials, a rate of translation is lower than the estimated 44 percent replication rate for highly cited human studies in Ioannidis (2005). Hackam recommends uniform reporting requirements and rigorous systematic reviews of animal experiments prior to human trials as potential solutions. [1a]

37. Hausheer FH, Kochat H, Parker AR, et al. New approaches to drug discovery and development: a mechanism-based approach to pharmaceutical research and its application to BNP7787, a novel chemoprotective agent. Cancer Chemother Pharmacol. 2003;52 Suppl 1:S3–15. [PubMed: 12819940]

In the face of poor predictivity of animal models and the “serendipity” of the compound screening process, the authors recommend an alternative approach to drug discovery, based on the elucidation and exploitation of biological, pharmacological, and biochemical mechanisms that have not been previously recognized or fully understood. Mechanism-based drug discovery (MBDR) involves the combined application of physics-based computer simulations and laboratory experimentation. MBDR research is based on the following principle: if a series of molecular simulations of the properties of a biological target, chemical transformations, stability and interactions, or drug–target interactions of interest are in agreement with a series of experimental observations of the molecular systems of interest, the corresponding probability that such observations are true and correct is greatly increased. This approach is aimed at reducing the probability of failure and enhancing the development process. [1b, 2b, 4a]

38. Hein WR, Griebel PJ. A road less traveled: large animal models in immunological research. Nat Rev Immunol. 2003;3:79–84. [PubMed: 12511878]

The authors argue that in immunological research there has been too much dependence on a single lab species (mice) that are, in critical ways, biologically irrelevant to the study of human disease and the development of therapies. They recommend placing greater emphasis on biological relevance and making use of large(r) animal models. [1c]

39. Herodin F, Thullier P, Garin D, et al. Nonhuman primates are relevant models for research in hematology, immunology and virology. Eur Cytokine Netw. 2005;16:104–16. [PubMed: 15941681]

Like Hein and Griebel (2003), the authors argue that the great similarity of nonhuman primates (NHPs) to humans justifies their use in the investigation of pathophysiological mechanisms in hematology, immunology and virology and in the evaluation of tolerance and efficacy of candidate therapeutics. Rodents are not sufficiently relevant to be able to predict human responsiveness to biological modifiers, pathogens, and potential therapeutics, notwithstanding the advantages conferred by the diversity of transgenic and knock-out murine models. Following a screening step in rodents, the availability of sophisticated cell and gene therapy tools makes it compulsory to validate them in preclinical trials with NHPs. [1c]

40. Hersch SM, Ferrante RJ. Translating therapies for Huntington’s disease from genetic animal models to clinical trials. NeuroRx. 2004;1:298–306. [PMC free article: PMC534928] [PubMed: 15717031]

The article examines what constitutes an informative genetic animal model (in neurological disease generally, and Huntington’s disease in particular), what principals should be followed in designing experiments using genetic models, and what constitutes sufficient mechanistic evidence to justify translation to humans. It includes useful discussion about importance of distinguishing between primary outcomes (neuropathological evidence of neuroprotection) and secondary outcomes (related to symptoms of Huntington’s disease). The impact therapeutic trials in genetic models can have on selecting compounds for clinical trials in humans depends on many factors relating to the quality and breadth of the preclinical data, captured in Figure 1 of the paper. [1a, 1c, 2a, 3b]

41. Horrobin DF. Modern biomedical research: an internally self-consistent universe with little contact with medical reality? Nat Rev Drug Discov. 2003;2(2):151–4. [PubMed: 12563306]

The author suggests that that biomedical science, and hence pharmaceutical science, has taken a wrong turn in its relationship to human disease. The information generated by cell culture, animal models of disease, transgenic mice and molecular biology studies rests on faulty and frequently unexamined assumptions and is not congruent with the “real world of medical illness.” Animal models “represent nothing more than an extraordinary, and in most cases irrational, leap of faith.” If we are to continue using animal models, at the very least we ought to test our assumptions by constantly referring back to the original disease in humans. [1a, 2a]

42. Hsu CY. Criteria for valid preclinical trials using animal stroke models. Stroke. 1993 May;24(5):633–6. [PubMed: 8257480]

This editorial addresses numerous challenges regarding study design and quality in the area of stroke research. The author suggests that the shortcomings inherent to clinical trials are often absent in animal experiments (lack of more objective outcome measures, diversity in stroke pathology, heterogeneity of demographic factors, comorbidities, variable delay in starting treatment). He argues that animal experiments should be held to the same rigorous design and conduct standards in place for clinical trials. [1a]

43. Insel TR. From animal models to model animals. Biol Psychiatry. 2007;62:1337–9. [PubMed: 18054535]

This editorial makes two points. First, it argues that biological psychiatry can learn much from modern comparative neurobiology, which studies the neural basis of species-typical behaviors rather than looking for phenocopies of human behavior. Second, it argues that traditional animal models might be mechanistically misleading, but the experimental use of model organisms (chosen strategically to test hypotheses) to understand the pathophysiology of mental disorders will be critical as clinical studies identify genetic alleles and cellular changes that confer risk for mental disorders. [1b, 2a]

44. Jeffery EH, Keck AS. Translating knowledge generated by epidemiological and in vitro studies into dietary cancer prevention. Mol Nutr Food Res. 2008;52 Suppl 1:S7–17. [PubMed: 18327874]

The article examines the lack of preclinical evidence in dietary cancer prevention, which lead to clinical trials that “provide confusing, disappointing, and maybe even harmful results.” The authors argue that once a poorly designed clinical trial fails to demonstrate a proposed benefit, it can take years and several trials to correct. They suggest that mechanistic evidence from in vitro studies and animal modeling of efficacy, bioavailability, and kinetics are essential for designing robust clinical trials. Figure 1 in the article describes authors’ view of standard and optimal approaches to scientific study of foods with health benefits. [1a, 2a, 3a]

45. Joers VL, Emborg ME. Preclinical assessment of stem cell therapies for neurological diseases. ILAR J. 2009;51:24–41. [PMC free article: PMC3075567] [PubMed: 20075496]

This article reviews the requirements of stem cell-based therapy for clinical translation, advances in stem cell research toward clinical application for neurological disorders, and different animal models used for analysis of these potential therapies (focusing on Parkinson’s disease, stroke and MS). Of particular interest for BMEBM is the discussion of the challenges in demonstrating the efficacy and safety of grafting human stem cells in animal models. [1c, 3a, 6]

46. Kamat CD, Gadal S, Mhatre M, et al. Antioxidants in central nervous system diseases: preclinical promise and translational challenges. J Alzheimers Dis. 2008;15:473–93. [PMC free article: PMC2669703] [PubMed: 18997301]

Recent high-profile failures of vitamin E trials in Parkinson’s disease, and nitrone therapies in stroke, have diminished enthusiasm to pursue antioxidant neuroprotectants in the clinic. The authors carefully consider whether the failures result from antioxidant theory or the implementation of that theory. The argue that evidence for the theory’s validity is convincing, but evidence of implementation flaws abound, including failure to understand the drug candidate’s mechanism of action in relationship to human disease, and failure to conduct preclinical studies using concentration and time parameters relevant to the clinical setting. [1a, 2a, 3b]

47. Kirschvink N, Reinhold P. Use of alternative animals as asthma models. Curr Drug Targets. 2008;9:470–84. [PubMed: 18537586]

This review focuses on the availability, advantages and nonadvantages of asthma models in nonlaboratory animals (cats, dogs, sheep, swine, cattle, horses, and monkey). The authors advocate for the use of these large animals because they offer the great potential to perform long-term functional studies allowing a simultaneous within-subject approach of functional, inflammatory and morphological changes. [1c]

48. Knight A. Animal experiments scrutinised: systematic reviews demonstrate poor human clinical and toxicological utility. ALTEX. 2007;24:320–5. [PubMed: 18288428]

49. Knight A. Systematic reviews of animal experiments demonstrate poor contributions toward human health care. Rev Recent Clin Trials. 2008;3:89–96. [PubMed: 18474018]

50. Knight A. Reviewing existing knowledge prior to conducting animal studies. Altern Lab Anim. 2008 Dec;36(6):709–12. [PubMed: 19154097]

In the above three papers, the author challenges the assumption that animal models provide an predictive basis which would justify their use in toxicity testing and biomedical research aimed at developing cures for human diseases. To investigate the validity of this assumption, he conducted a search of SCOPUS databases for published systematic reviews of the human clinical or toxicological utility of animal experiments. Of 20 reviews examining clinical utility, authors concluded that the animal models were substantially consistent with or useful in advancing clinical outcomes in only 2 cases. Possible causes include interspecies differences, the distortion of experimental outcomes arising from experimental environments and protocols, and the poor methodological quality of many animal experiments. While the latter problems might be minimized, the interspecies limitations may be technically and theoretically impossible to overcome. Yet, unlike nonanimal models, animal models are not normally subjected to formal scientific validation. The author argues that instead of simply assuming they are predictive of human outcomes, the consistent application of formal validation studies to all test models is clearly warranted. [1a, 2a]

51. Ledford H. Translational research: the full cycle. Nature. 2008;453:843–5. [PubMed: 18548044]

This journalistic article examines the notion of reverse translation—that clinical trials and patients’ unexpected responses are valuable human experiments, and failed trials can stimulate new hypotheses that may help refine the experiment in its next iteration. This “bedside to bench” approach is explained through the recounting of three clinical trials (cancer drug, gene therapy, HIV vaccine). [1a]

52. Lemon R, Dunnett SB. Surveying the literature from animal experiments. BMJ. 2005;330:977–8. [PMC free article: PMC557132] [PubMed: 15860802]

In this editorial, the authors take the view that a review of all known relevant preclinical experiments should be conducted prior to human clinical trials. They recommend performing what they call a “critical review” rather than a systematic review. A critical review compiles and evaluates the different sources of experimental evidence on a qualitative basis. A difficulty with systematic reviews is that attempts to meet precise inclusion criteria often mean useful information is excluded. They argue that the reliability and validity of each animal model needs to be assessed on its merits and its relevance to the particular clinical application. [1a]

53. Linder S, Shoshan MC. Is translational research compatible with preclinical publication strategies? Radiat Oncol. 2006;1:4. [PMC free article: PMC1459183] [PubMed: 16722592]

In this paper, the authors examine translational difficulties in the area of cancer therapeutics. They argue that a number of factors contribute to making the translation process inefficient, including the use of sensitive cell lines and fast growing experimental tumors as targets for novel therapies, and the use of unrealistic drug concentrations and radiation doses. They suggest that the aggressive interpretation of data, successful in hypothesis-building biological research, does not form a solid base for development of clinically useful treatment modalities, and question whether “clean” results obtained in simplified models, expected for publication in high-impact journals, represent solid foundations for improved treatment of patients. They recommend increasing open-access publishing to increase dissemination and transparency of all relevant data. [1a, 3a]

54. Lindner MD. Clinical attrition due to biased preclinical assessments of potential efficacy. Pharmacol Ther. 2007;115:148–75. [PubMed: 17574680]

This article examines the magnitude and prevalence of numerous biases that may affect preclinical assessments of potential efficacy. The author argues that the shift to more target-based drug discovery has increased bias, suggesting that proof of concept studies that used to be conducted fairly early, before strong attachments to individual targets had developed, are now conducted at the end of the lead optimization phase, 3 to 5 years into the program, at a point when considerable time and resources have already been invested. He recommends a number of ways to limit bias (cultural, procedural, decision-making). [1a]

55. Loscher W. Preclinical assessment of proconvulsant drug activity and its relevance for predicting adverse events in humans. Eur J Pharmacol. 2009;610:1–11. [PubMed: 19292981]

This article compares preclinical and clinical models for the assessment of proconvulsant activity of investigational or marketed drugs. The author argues that a major limitation of tests to assess the safety of various agents is the specific mechanism of action of convulsant effect, so that testing of drugs may produce both false positive and false negative data, and argues for a different set of tests that can provide complete and more reliable conclusions about the proconvulsant potential of an investigational drug. These tests should include animals with lowered seizure threshold, and consider the relation of doses producing (pro)convulsant effects to the therapeutic dose-range of a substance (“therapeutic index”). [1b, 6]

56. Lowenstein PR, Castro MG. Uncertainty in the translation of preclinical experiments to clinical trials: Why do most Phase III clinical trials fail? Current Gene Therapy. 2009;9:368–74. [PMC free article: PMC2864134] [PubMed: 19860651]

This paper assesses why so few Phase III clinical trials have failed in translation from preclinical experiments. It briefly describes some of the complications of preclinical experimentation generally (availability of numerous types of models, each with own advantages and disadvantages; human patients having been exposed to the “standard of care” prior to the novel therapy; statistical issues, including over-reliance on p<0.05 and failure to analyze effect size); genetic homogeneity of experimental animals; scaling; disease time course). The authors suggest that a main limitation of the basic science is the “lack of comprehensive understanding of which variables being examined are actually significant and/or rate limiting parameters that are relevant to the study of human disease, and predictive of novel treatments’ efficacy in human patients.” They provide recommendations for how the process from preclinical experiments to RCTs can be made more “robust,” defined as an experimental system’s ability to “maintain its central functions in the face of challenges.” They recommend preclinical testing in a variety of models in different genetic backgrounds, ages, sizes, and species, to show whether efficiency seen in a homogenous genetic background is robust viz. genetic heterogeneity. They also recommend that early phase trials should be designed to simultaneously target safety and treatment efficacy, not just safety as is currently the case. The authors do not propose specific ways of better capturing/evaluating preclinical evidence, but suggest that developments in mathematical, statistical and biological models will allow for more rigorous assessment of such evidence. [1a, 1b, 3a]

57. Lynch VJ. Use with caution: developmental systems divergence and potential pitfalls of animal models. Yale J Biol Med. 2009;82:53–66. [PMC free article: PMC2701150] [PubMed: 19562005]

The author of this article challenges the assumption that gene functions and genetic systems are conserved between models and humans, arguing that evidence that gene functions and networks diverge during evolution is often overlooked. A number of mechanisms that generate functional divergence and recent examples demonstrating that gene functions and regulatory networks diverge through time are presented. The author argues that the examples suggest that annotation of gene functions based solely on mutant phenotypes in animal models, as well as assumptions of conserved functions between species, can be wrong. Therefore, animal models of gene function and human disease may not provide appropriate information, particularly for rapidly evolving genes and systems. [2a]

58. Macleod MR, Ebrahim S, Roberts I. Surveying the literature from animal experiments: systematic review and meta-analysis are important contributions. BMJ. 2005;331:110. [PMC free article: PMC558663] [PubMed: 16002897]

59. Macleod MR, Fisher M, O’Collins V, et al. Good laboratory practice: preventing introduction of bias at the bench. Stroke. 2009;40:e50–2. [PubMed: 18703798]

60. Macleod MR, O’Collins T, Howells DW, et al. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke. 2004;35:1203–8. [PubMed: 15060322]

61. Macleod MR, van der Worp HB, Sena ES, et al. Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke. 2008;39:2824–9. [PubMed: 18635842]

In the above four papers, Macleod and colleagues present empirical evidence of bias and poor study quality in the area of ischemic stroke. On the contrary, Lemon and Dunnett (2005) argue that quantitatively-oriented systematic reviews and meta-analyses are preferable to a “critical” review approach. They propose a series of measures/practices aimed at reducing bias in preclinical stroke experiments including randomization, allocation concealment, sample size calculations, and blinded assessment of outcome. The two systematic reviews of neuroprotective agents demonstrate that preclinical reports of efficacy are confounded by study quality biases. [1a]

62. Malkesman O, Austin DR, Chen G, Manji HK. Reverse translational strategies for developing animal models of bipolar disorder. Dis Model Mech. 2009;2:238–45. [PMC free article: PMC2675806] [PubMed: 19407332]

The article highlights a number of issues relevant to BMEBM. One is that the phenotypical complexity of human disease, particularly in the case of bipolar disorder (BD), is rarely captured in preclinical animal models, which rely on simpler phenotypes. The authors use three criteria—face validity, predictive validity, and construct validity—to evaluate animal models in BD, suggesting that construct validity allows researchers to generate a possible common mechanistic theory that can explain both the animal model and the human disorder. They suggest using construct validity, rather than face validity, as a starting point for creating models, capitalizing on technological advances that allow researchers to create animal models that reflect the biological changes observed in studies of individuals with BD. They believe that this strategy, while imperfect, will help to support valid hypotheses regarding the mechanisms of BD. [1a, 1b, 3a]

63. Manger PR, Cort J, Ebrahim N, et al. Is 21st century neuroscience too focused on the rat/mouse model of brain function and dysfunction? Front Neuroanat. 2008;2:5. [PMC free article: PMC2605402] [PubMed: 19127284]

This paper presents an analysis that demonstrates that 75 percent of neuroscience research efforts are directed to the rat, mouse, and human brain, or 0.0001 percent of the nervous systems on the planet. This extreme bias in research trends may provide a limited scope in the discovery of novel aspects of brain structure and function that would be of importance in understanding both the evolution of the human brain and in selecting appropriate animal models for use in clinically relevant research of mental illnesses. [1b, 2a]

64. Manto M, Marmolino D. Animal models of human cerebellar ataxias: a cornerstone for the therapies of the twenty-first century. Cerebellum. 2009;8:137–54. [PubMed: 19669387]

65. Manto M, Marmolino D. Cerebellar disorders—at the crossroad of molecular pathways and diagnosis. Cerebellum. 2009;8:417–22. [PubMed: 19859773]

These two articles provide a largely uncritical review of developments concerning preclinical models of cerebellar ataxias. These models have yielded significant breakthroughs in our understanding of the pathogenesis of cerebellar ataxias (especially at molecular level), reproducing to various extents human brain disorders. The authors are hopeful that these findings will be integrated into clinical research and that therapeutic strategies will move beyond merely the treatment of symptoms. [1c, 2a]

66. Mao J. Translational pain research: achievements and challenges. J Pain. 2009;10:1001–11. [PMC free article: PMC2757533] [PubMed: 19628433]

This article reviews the advances made in recent pain research and examines the translational gaps between pain mechanisms and clinical pain. The author considers potential causes of these gaps, both from bench to bedside (experimental conditions, PK/PD issues such as dosage and bioavailability, discrepancy in pain assessment tools, comorbidity/gender/genetic differences) and bedside to bench (experimental pain models, spontaneous vs. stimulus-induced pain, acute vs. chronic pain). The author identifies the development of objective pain-assessment tools as a fundamentally important goal of pain research. [1a, 3a]

67. Markou A, Chiamulera C, Geyer MA, et al. Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology. 2009;34:74–89. [PMC free article: PMC2651739] [PubMed: 18830240]

The article discusses the traditional role of animal models in neuroscience drug discovery (focused mainly on psychiatric, as opposed to neurological disorders) and the reasons why this approach has led to suboptimal utilization of the information that animal models provide. Certain experiments and recombinant DNA technologies (creating knockout mice) are widely-used, but their predictive validity for clinical benefit has not been critically examined. Preclinical and clinical measures need to assess as closely as possible homologous, or at least analogous, biological variables. The authors argue that such correspondence between preclinical and clinical measures will greatly enhance predictability, and thus promote translation back and forth between animal and human studies. Furthermore, the measures used both preclinically and clinically should have construct validity, defined as measuring accurately the theoretical behavioral and neurobiological variables that are considered core to the disorder of interest. [1a, 2a]

68. Marshall JC, Deitch E, Moldawer LL, et al. Preclinical models of shock and sepsis: what can they tell us? Shock. 2005;24 Suppl 1:1–6. [PubMed: 16374365]

The authors of this paper argue that while preclinical models of shock and sepsis do not predict therapeutic efficacy in human disease, they provide insights that may be of use in deciding whether a strategy is worth evaluating in the clinical arena, and if so, in which patients and under what circumstances. These models can also point to potential adverse effects that may limit the use of that strategy in particular groups of patients. Table 4 in the paper outlines an approach to the development of a portfolio of preclinical models that is especially insightful. [1a, 3b, 6]

69. Matthews RA. Medical progress depends on animal models—doesn’t it? J R Soc Med. 2008;101:95–98. [PMC free article: PMC2254450] [PubMed: 18299631]

The author proposes a calculation to assess the evidential weight provided by animal models. This can be done using the concepts of sensitivity (i.e., the true positive rate) and specificity (i.e., true negative rate). These lead to various ways of quantifying evidential weight, of which the most direct and transparent is the likelihood ratio (LR), whose definition is such that only tests producing LR >1 can be deemed to have contributed any weight of evidence. The paucity of quantitative comparative data for animal models makes even such simple calculations impossible. The author offers numerous explanations for this paucity: (1) compounds that produce unacceptable effects in animal models will not progress to human trials, making studies capable of giving sensitivity/false positive rates for animal models ethically problematic; (2) it is frequently difficult to establish end-points sufficiently clear-cut to allow categorization as true positives or true negatives; (3) much of the comparative animal-human data is obtained under conditions of commercial confidentiality. [1a]

70. Miczek KA, de Wit H. Challenges for translational psychopharmacology research—some basic principles. Psychopharmacology (Berl) 2008;199:291–301. [PubMed: 18523737]

This thoughtful paper lays out a number of principles for translating preclinical findings to clinical applications in the area of psychopharmacological drug development. The key challenge –particularly acute in research on psychiatric disorders — is that few models of psychiatric disorders are homologous with the disorder; rather the laboratory procedures model isomorphic signs and symptoms. The principles of note for BMEBM purposes include:

  1. The translation of preclinical data to clinical concerns is more successful when the scope of experimental models is restricted to a core symptom of a psychiatric disorder.

  2. Preclinical experimental models gain in clinical relevance if they incorporate conditions that induce maladaptive behavioral or physiological changes that have some correspondence with species-normative behavioral adaptations.

  3. Preclinical data are more readily translated to the clinical situation when they are based on converging evidence from several experimental procedures, each capturing cardinal features of the disorder.

  4. The more closely a model approximates significant clinical symptoms, the more likely it is to generate data that will yield clinical benefits.

  5. The choice of environmental, genetic, and/or physiological manipulations that induce a cardinal symptom or cluster of behavioral symptoms reveals the theoretical approach used to construct the model.

  6. Preclinical experimental preparations that are validated by predicting treatment success with a prototypic agent are only able to detect alternative treatments that are based on the same mechanism as the existing treatment that was used to validate the screen.

  7. The degree to which an experimental model fulfills the criteria of high construct validity relative to face or predictive validity depends on the purpose of the model. [1b, 2a, 3b]

71. Mignini LE, Khan KS. Methodological quality of systematic reviews of animal studies: a survey of reviews of basic research. BMC Med Res Methodol. 2006;6:10. [PMC free article: PMC1435907] [PubMed: 16533396]

This paper reports a review of systematic reviews of animal studies and found the methodological rigor of the systematic reviews lacking in terms of their assessment of study validity and quality. The authors found that reviews often lacked methodological features such as specification of a testable hypothesis, assessment of publication bias, study validity and heterogeneity, and meta-analysis for quantitative synthesis. They assert that there is a need for more rigor in reviewing animal research. [1a]

72. Mitchell BF, Taggart MJ. Are animal models relevant to key aspects of human parturition? Am J Physiol Regul Integr Comp Physiol. 2009;297:R525–45. [PubMed: 19515978]

This article critically reviews the data and concepts concerning the use of animal models for parturition and offers a rationale for the use of a new model. A number of animal models have contributed to advances in understanding the regulation of parturition. The authors suggest that animals dependent on progesterone withdrawal to initiate parturition clearly have a limitation to their translation to the human. In these models, a linear sequence of events gives rise to a “trigger” mechanism. The authors propose that human parturition arises from the maturation of several systems in parallel, and emphasize the need to determine the precise role of the immune system in the process of parturition. They support the development of nonprimate animal models whose physiology is more relevant to human parturition (guinea pig) and who display key physiological characteristics of gestation that more closely resemble human pregnancy than do currently favored animal models. [1c, 2a]

73. Mogil JS. Animal models of pain: progress and challenges. Nat Rev Neurosci. 2009;10:283–94. [PubMed: 19259101]

This paper reviews the state of the art regarding behavioral animal models of pain. There is a useful discussion and defense of why animal models are needed in this area of research, which includes a brief discussion of clinical face validity. Box 1 in the paper offers some conceptual clarification, re: what we mean in using the term “animal model,” distinguishing between the subject, the assay, and the measure. The authors also highlight the disconnect between preclinical experiments (where young, male animals are used) and the epidemiological evidence of human pain (typical chronic-pain patient is middle-aged and female). [1a, 2a, 3a]

74. Muschler GF, Raut VP, Patterson TE, et al. The design and use of animal models for translational research in bone tissue engineering and regenerative medicine. Tissue Eng Part B Rev. 2010 Feb;16(1):123–45. [PubMed: 19891542]

This article provides an overview of animal models for the evaluation, comparison, and systematic optimization of tissue engineering and regenerative medicine strategies related to bone tissue. It includes an overview of major factors that influence the rational design and selection of an animal model. Two sections of the paper are of import to BMEBM. One describes “missing links” between preclinical and clinical performance, including: underestimation of variation in clinical response, overestimation of performance, and insensitivity to incremental improvement. In a section (re: “gaps and opportunities “ to improve existing models) the authors identify gaps in the availability of animal models, including: (1) the need for assessment of the predictive value of preclinical models for relative clinical efficacy, (2) the need for models that more effectively mimic the wound healing environment and mass transport conditions in the most challenging clinical settings, and (3) the need for models that allow better measurement and detection of cell trafficking events and ultimate cell fate. [1c, 3a, 3b]

75. O’Collins VE, Macleod MR, Donnan GA, et al. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59:467–77. [PubMed: 16453316]

This systematic review sought to identify agents tested in animal neuroprotection models and those treatments given to acute stroke patients; and to compare the overall quality of evidence and experimental efficacy of those treatments that have been given to acute stroke patients and those agents that have not progressed beyond the experimental phase. The numerous findings and recommendations related to poor study design and quality are significant. All told, there was no evidence that drugs used clinically were more effective experimentally than those tested only in animal models. Moreover, no particular mechanism of action in animal models demonstrated superior efficacy, leading the authors to suggest that the current stroke models are in need of reformulation. The authors argue that intervention should be considered for clinical trial only when there is both a high level of experimental efficacy and a diverse body of evidence supporting its clinical application. [1a, 2a]

76. Opal SM, Patrozou E. Translational research in the development of novel sepsis therapeutics: logical deductive reasoning or mission impossible? Crit Care Med. 2009;37:S10–5. [PubMed: 19104207]

Like Marshall et al. (2005), the authors highlight some of the translational challenges of sepsis research. They discuss a number of technological advances that may allow for more realistic technology recapitulation of events in the pathophysiology of sepsis, which may assist in the preclinical evaluation of antisepsis drugs. In the short term, they advocate using the PIRO concept (predisposing factors, infection type, host response, and organ dysfunction model) to deal with the multiple parameters that affect outcome in sepsis (see Table 2 in paper). Animal models should take at least some of these factors in consideration in the design of preclinical programs to study new antisepsis agents. [1b, 2a, 3a]

77. Pacharinsak C, Beitz A. Animal models of cancer pain. Comp Med. 2008;58:220–33. [PMC free article: PMC2704117] [PubMed: 18589864]

This article reviews a number of recently developed models of cancer pain. While earlier models examined anatomic mechanisms, recent models (mostly rodent, but some feline and canine models) are examining basic biochemical, molecular, and neurobiologic mechanisms. These models — which allow researchers to generate novel hypotheses regarding the roles of genes and their protein products in pain processing and modulation — will be crucial to developing novel therapeutic drugs that specifically target particular genes for specific types of cancer pain. [1c, 2a, 2d, 3a]

78. Palena C, Abrams SI, Schlom J, Hodge JW. Cancer vaccines: preclinical studies and novel strategies. Adv Cancer Res. 2006;95:115–45. [PubMed: 16860657]

This article reviews findings from preclinical cancer vaccine studies conducted in animal tumor models. While progress in understanding the molecular mechanisms of immune activation has helped in the design of novel and more efficient vaccine strategies, the authors contend that major translational challenges remain. One is related to the relevance of the utilized models. Most preclinical work to date has been conducted with transplanted murine tumors that grow rapidly, are usually noninvasive, and fail to metastasize. Most human tumors grow slowly and do not represent the percent of body mass that murine tumors do. The short time span of mouse models precludes multiple booster vaccinations, so few cycles of vaccine immunotherapy can be given. This is in contrast to the vaccine therapy in a patient with minimal residual disease, who can receive many cycles of immunotherapy over the course of several years. A second challenge is related to the fact that many defined tumor antigens are self-proteins and therefore generally fail to initiate strong antitumor T-cell responses. Thus, a key for developing successful cancer vaccines is to overcome potential mechanisms of immune suppression against antigenic but weakly immunogenic tumors. [1c, 2a, 3a]

79. Pegram M, Ngo D. Application and potential limitations of animal models utilized in the development of trastuzumab (Herceptin): a case study. Adv Drug Deliv Rev. 2006;58:723–34. [PubMed: 16876287]

This article presents a case study of trastuzumab with a focus on the role of animal models in many phases of the drug’s development. The authors review what was learned from murine models to understand the pathogenesis of breast cancer, test efficacy of various monoclonal anti-HER2 antibodies, and to provide insight into the mechanism of action of the drug. The principle shortcoming of animal modeling in the development of trastuzumab was the lack of cross reactivity of trastuzumab to nonhuman HER2, making it difficult, if not impossible, to predict unanticipated toxicities such as cardiac dysfunction. [1a, 3a, 6]

80. Perel P, Roberts I, Sena E, et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ. 2007;334:197. [PMC free article: PMC1781970] [PubMed: 17175568]

The Living Bibliography of Animal Studies

As the field of animal studies continues to grow it is becoming more and more difficult to keep up with new publications. This is a particularly pressing problem given the interdisciplinary nature of the field. How can an individual with a specialism in literary studies, for example, hope to know what is cutting edge in animal geography when she is struggling to keep up with her own field? How can a newcomer know where to start when there are so many different ways in? The living bibliography is a forum that attempts to offer one way of addressing this problem.

LBAS is influenced by the JISC -funded ‘Living Books About Life’ series published by Open Humanities Press. Clare Birchall, Garry Hall and Joanna Zylinska who edited the series have written that ‘All the books … are themselves ‘living’, in the sense that they are open to ongoing collaborative processes of writing, editing, updating, remixing and commenting by readers’. The same active reading, amending, and adding are encouraged here.

The initial LBAS includes invited responses from a number of leading scholars in the field, from a range of disciplines. The bibliographies that they have written are suggestive: the opening gambit in what we hope will be an ongoing process. The scholar who compiled each list will be named, and we hope that this will continue. Selection of and comments on books and essays are useful in and of themselves, but it will be interesting, as well, to know who they came from.

The software will allow registered users to:

  • Comment on existing bibliographies;
  • Add to existing bibliographies – in terms of other references, or a new, more specialist subsection;
  • Link texts from one disciplinary bibliography to another to begin to show how works in the field of animal studies might be transcending the institutional enclaves we all work within;
  • Start up a new list – from an absent discipline or field, or from an area that will benefit from not being held within disciplinary boundaries. This might include, for example, work on pets; or on animals and postcolonialism.

As the bibliography grows and matures it is hoped that it will move from focusing on works that scholars have found particularly productive towards a fuller coverage of the field. Full coverage is not the immediate aim, but it is hoped that LBAS will provide a stepping off point for scholars new to the field, as well as a source of information and ideas for those more familiar. It might also offer evidence of the important scholarship that is emerging out of the study of human-animal relations, and will show how the field has developed and is developing; where new interests lie; what areas are declining. As such, LBAS might also help us to track what it is that animal studies has been, is, and might become.

As ever: politeness is key, and any and all offensive postings will be refused. So please be nice. Scholarly criticism can (and should) be done with tact.

Thanks to the following for constructing the initial bibliographies:

Steve Baker (Contemporary Art); Bruce Boehrer (Renaissance Studies); Brett Buchanan (Continental Philosophy); Henry Buller (Animal Geography); David Clough (Religious Studies and Theology); Susan Crane (Medieval Studies); Susan Curry (Classical Studies); Diana Donald (Art History); Monica Mattfeld (Eighteenth-Century Studies); Erica Fudge (Historical Studies); Robert Garner (Politics); Garry Marvin (Anthropology); Susan McHugh (Contemporary Literature); John Miller (Victorian Studies); Claire Molloy (Media Studies); Clare Palmer (Analytic Ethics); Annie Potts (Cultural Studies); Fiona Probyn-Rapsey (Gender Studies); Lourdes Orozco (Theatre Studies); Tom Tyler (Videogaming); Rhoda Wilkie (Sociology); Abigail Woods (Veterinary History);


Instructions on how to add references and comments to lists can be found here. Please read these carefully before attempting to add to the website.

To join the community of scholars on this website please click the 'log in' link at the top right of this page and complete the form. Once your request is processed you will receive an email confirming that access has been granted. When you receive this you will be able to login to the wiki and add your own bibliographical suggestions. This approval process is done by a human being rather than a computer so may take a little time. Please be patient. Please remember: all additions to the website must abide by the rules set out in the Instructions found here. Thanks.


Now, let it live …

The bibliography is funded by the Faculty of Humanities and Social Sciences, University of Strathclyde, and is linked to the British Animal Studies Network. It is, like BASN, under the direction of Erica Fudge, and was started as part of her AHRC Leadership Fellowship (2015-16).

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