Predictive Value Of Animal Models Research Articles

Levelling the Translational Gap for Animal to Human Efficacy Data

Simple SummaryThe value of animal research has been increasingly debated, owing to high failure rates in drug development. A potential contributor to this situation is the lack of predictivity of animal models of disease. Until recently, most initiatives focused on well-known problems related to the lack of reproducibility and poor reporting standards of animal studies. Only now, more methodologies are becoming available to evaluate how translatable the data from animal models of disease are. We discuss the use and implications of several methods and tools to assess the generalisability of animal data to humans. To analyse the relevance of animal research objectively, we must (1) guarantee the experiments are conducted and reported according to best practices; (2) ensure the selection of animal models is made with a clear and detailed translational rationale behind it. Once these conditions are met, the true value of the use of animals in drug development can be finally attested.Reports of a reproducibility crisis combined with a high attrition rate in the pharmaceutical industry have put animal research increasingly under scrutiny in the past decade. Many researchers and the general public now question whether there is still a justification for conducting animal studies. While criticism of the current modus operandi in preclinical research is certainly warranted, the data on which these discussions are based are often unreliable. Several initiatives to address the internal validity and reporting quality of animal studies (e.g., Animals in Research: Reporting In Vivo Experiments (ARRIVE) and Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (PREPARE) guidelines) have been introduced but seldom implemented. As for external validity, progress has been virtually absent. Nonetheless, the selection of optimal animal models of disease may prevent the conducting of clinical trials, based on unreliable preclinical data. Here, we discuss three contributions to tackle the evaluation of the predictive value of animal models of disease themselves. First, we developed the Framework to Identify Models of Disease (FIMD), the first step to standardise the assessment, validation and comparison of disease models. FIMD allows the identification of which aspects of the human disease are replicated in the animals, facilitating the selection of disease models more likely to predict human response. Second, we show an example of how systematic reviews and meta-analyses can provide another strategy to discriminate between disease models quantitatively. Third, we explore whether external validity is a factor in animal model selection in the Investigator’s Brochure (IB), and we use the IB-derisk tool to integrate preclinical pharmacokinetic and pharmacodynamic data in early clinical development. Through these contributions, we show how we can address external validity to evaluate the translatability and scientific value of animal models in drug development. However, while these methods have potential, it is the extent of their adoption by the scientific community that will define their impact. By promoting and adopting high quality study design and reporting, as well as a thorough assessment of the translatability of drug efficacy of animal models of disease, we will have robust data to challenge and improve the current animal research paradigm.

A PBMC-Based System to Assess Human T Cell Responses to Influenza Vaccine Candidates In Vitro.

Vaccine development is an expensive and time-consuming process that heavily relies on animal models. Yet, vaccine candidates that have previously succeeded in animal experiments often fail in clinical trials questioning the predictive value of animal models. Alternative assay systems that can add to the screening and evaluation of functional characteristics of vaccines in a human context before embarking on costly clinical trials are therefore urgently needed. In this study, we have established an in vitro system consisting of long-term cultures of unfractionated peripheral blood mononuclear cells (PBMCs) from healthy volunteers to assess (recall) T cell responses to vaccine candidates. We observed that different types of influenza vaccines (whole inactivated virus (WIV), split, and peptide vaccines) were all able to stimulate CD4 and CD8 T cell responses but to different extents in line with their reported in vivo properties. In-depth analyses of different T cell subsets revealed that the tested vaccines evoked mainly recall responses as indicated by the fact that the vast majority of the responding T cells had a memory phenotype. Furthermore, we observed vaccine-induced activation of T follicular helper cells, which are associated with the induction of humoral immune responses. Our results demonstrate the suitability of the established PBMC-based system for the in vitro evaluation of memory T cell responses to vaccines and the comparison of vaccine candidates in a human immune cell context. As such, it can help to bridge the gap between animal experiments and clinical trials and assist in the selection of promising vaccine candidates, at least for recall antigens.

What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? Consideration of Strategies to Improve the Value of Animal Models.

Animal models are an essential feature of the vaccine design toolkit. Although animal models have been invaluable in delineating the mechanisms of immune function, their precision in predicting how well specific vaccines work in humans is often suboptimal. There are, of course, many obvious species differences that may limit animal models from predicting all details of how a vaccine works in humans. However, careful consideration of which animal models may have limitations should also allow more accurate interpretations of animal model data and more accurate predictions of what is to be expected in clinical trials. In this article, we examine some of the considerations that might be relevant to cross-species extrapolation of vaccine-related immune responses for the prediction of how vaccines will perform in humans.

What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? The Importance of Bridging Studies and Species-Independent Correlates of Protection.

Animal models have played a pivotal role in all stages of vaccine development. Their predictive value for vaccine effectiveness depends on the pathogen, the robustness of the animal challenge model, and the correlates of protection (if known). This article will cover key questions regarding bridging animal studies to efficacy trials in humans. Examples include human papillomavirus (HPV) vaccine in which animal protection after vaccination with heterologous prototype virus-like particles (VLPs) predicted successful efficacy trials in humans, and a recent approval of anthrax vaccine in accordance with the "Animal Rule." The establishment of animal models predictive of vaccine effectiveness in humans has been fraught with difficulties with low success rate to date. Challenges facing the use of animal models for vaccine development against Ebola and HIV will be discussed.

What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? Reevaluating the Potential of Mouse Models for the Human Immune System.

Much of what we understand about immunology, including the response to vaccines, come from studies in mice because they provide many practical advantages compared with research in higher mammals and humans. Nevertheless, modalities for preventing or treating disease do not always translate from mouse to humans, which has led to increasing scrutiny of the continued merits of mouse research. Here, we summarize the pros and cons of current laboratory mouse models for immunology research and discuss whether overreliance on nonphysiological, ultra-hygienic animal husbandry approaches has limited the ultimate translation potential of mouse-derived data to humans. Alternative approaches are discussed that may extend the use of the mouse model for preclinical studies.

What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans?

Simian immunodeficiency virus (SIV) challenge of rhesus macaques provides an invaluable tool to evaluate the clinical prospects of HIV-1 vaccine concepts. However, as with any animal model of human disease, it is crucial to understand the advantages and limitations of this system to maximize the translational value of SIV vaccine studies. Here, we discuss the importance of assessing the efficacy of vaccine prototypes using stringent SIV challenge regimens that mimic HIV-1 transmission and pathogenesis. We also review some of the cautionary tales of HIV-1 vaccine research because they provide general lessons for the preclinical assessment of vaccine candidates.

Development of Novel Agents for Idiopathic Pulmonary Fibrosis: Progress in Target Selection and Clinical Trial Design

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease. Until recently, the standard therapy for this disease has been essentially supportive, with the exception of a minority of patients who were eligible for lung transplantation. The development pathway for novel medications for IPF has been complicated. There have been several challenges, including an incomplete understanding of the pathogenesis, unpredictable clinical course, lack of validated biomarkers, the low clinical predictive value of animal models of lung injury, and the need to commit to large clinical trials of long duration to obtain initial evidence of clinical efficacy. Despite these challenges, the combination of recent advances in translational medicine and the unprecedented increase in clinical data accumulated from recent large clinical trials has stimulated an increase in the number of clinical development programs for IPF. Clinical programs are increasingly characterized by rational target selection, preclinical optimization of therapeutic molecules, and an emphasis on efficient clinical trial design. A lower rate of functional decline in patients treated with pirfenidone and nintedanib was demonstrated in large clinical trials. In October 2014, these two drugs became the first agents to be approved by the US Food and Drug Administration for the treatment of IPF. (Pirfenidone had already been approved in several countries outside the United States.) In November 2014, the European Medicines Agency approved the use of nintedanib for IPF. The landscape for management of IPF has markedly changed with the advent of approved therapeutic options for IPF. In this article, we review the strategies that are being used to increase the likelihood of success in clinical development programs of novel disease-modifying agents in IPF.

The Ethical Implications for Humans in Light of the Poor Predictive Value of Animal Models

The notion that animals could be used as predictive models in science has been influenced by relatively recent developments in the fields of complexity science, evolutionary and developmental biology, genetics, and evolutionary biology in general. Combined with empirical evidence, which has led scientists in drug development to acknowledge that a new, nonanimal model is needed, a theory—not a hypothesis—has been formed to explain why animals function well as models for humans at lower levels of organization but are unable to predict outcomes at higher levels of organization. Trans-Species Modeling Theory (TSMT) places the empirical evidence in the context of a scientific theory and thus, from a scientific perspective, the issue of where animals can and cannot be used in science has arguably been settled. Yet, some in various areas of science or science-related fields continue to demand that more evidence be offered before the use of animal models in medical research and testing be abandoned on scientific grounds. In this article, I examine TSMT, the empirical evidence surrounding the use of animal models, and the opinions of experts. I contrast these facts with the opinions and positions of those that have a direct or indirect vested interest—financial or otherwise—in animal models. I then discuss the ethical implications regarding research constructed to find cures and treatments for humans.

The Nuremberg Code subverts human health and safety by requiring animal modeling

BackgroundThe requirement that animals be used in research and testing in order to protect humans was formalized in the Nuremberg Code and subsequent national and international laws, codes, and declarations.DiscussionWe review the history of these requirements and contrast what was known via science about animal models then with what is known now. We further analyze the predictive value of animal models when used as test subjects for human response to drugs and disease. We explore the use of animals for models in toxicity testing as an example of the problem with using animal models.SummaryWe conclude that the requirements for animal testing found in the Nuremberg Code were based on scientifically outdated principles, compromised by people with a vested interest in animal experimentation, serve no useful function, increase the cost of drug development, and prevent otherwise safe and efficacious drugs and therapies from being implemented.

Animal Models in Cardiovascular MRI Research: Value and Limitations

This review will explore the interface between MRI, cardiovascular research, and animal models, with particular attention to values, limitations, and best practices. This includes the question of whether an animal model may be necessary or appropriate. Factors influencing the selection of small versus large animal models will be considered, including the features that distinguish mice from other animal models. MRI has proven extremely useful in studies of basic cardiovascular physiology, but its true utility lies in the acquisition of end points relevant to cardiovascular disease in preclinical and clinical investigations. Brief summaries will be presented of the many anatomic and functional parameters that can be assessed by cardiovascular MRI, along with its role in translational medicine. Finally, the predictive value and clinical relevance of animal models of cardiovascular disease will be explored, including steps that are recommended to maximize the predictive value of animal models in translational medicine.

Videoradiographic analysis of the range of motion in unilateral experimental knee joint arthritis in rats

IntroductionThe translational and predictive value of animal models highly depends on the validity of respective readout parameters. In arthritis research, there has been a shift from sole threshold testing for pain-related behavior, as well as from swelling and histology assessment for inflammation, toward an analysis of joint function as indicated, for instance, by an increasing number of studies on gait abnormalities. Clinically, the range of motion (ROM) of the affected joint plays a major role in diagnosis and the assessment of treatment benefits. This parameter, however, is only insufficiently detected by currently used analytic systems in animals.MethodsHere we used high-resolution videoradiographic analysis to assess ROM in experimental knee joint arthritis in rats. This parameter is described during the 21-day course of antigen-induced arthritis in rats. Furthermore, the therapeutic effects of antinociceptive (morphine) and anti-inflammatory (dexamethasone) treatment on ROM are documented. To obtain additional information on the implications of ROM in animal models, correlations were performed to measure pain-related behavior and inflammation.ResultsThe study animals showed a significant reduction in ROM of the inflamed knee joint in the acute phase of arthritis. This was accompanied by an increase in knee joint movement on the contralateral side, indicating a compensational mechanism. Both morphine and dexamethasone treatment increased and thus normalized ROM. Changes in ROM were further stage-dependently correlated with weight bearing and joint swelling, that is, with both pain-related behavior and signs of inflammation.ConclusionsThe dynamic ROM observed in freely moving rats in our model of knee joint arthritis might serve as a parameter for global disease activity and might thus represent a promising readout parameter for preclinical assessment regarding the overall efficacy not only of antiarthritic but also of antinociceptive compounds.

How Good Are Current Approaches to Nonclinical Evaluation of Abuse and Dependence?

Nonclinical assessment of drug abuse and dependence is the subject of several recent regulatory guidelines, which are generally aligned on the methods to be employed. The most direct approach to assessing reinforcing properties of a drug is the self-administration procedure whereby animals can initiate intravenous injections of the test substance, something they readily do with prototypic drugs of abuse. Complications arise because there is no standardized procedure for evaluating substances with differing potencies, reinforcement properties, or pharmacokinetics. Moreover, the choice of training substance, species, and procedural parameters can radically affect the outcome. Apart from the lower cost of rats, primates present several advantages for self-administration studies with similarity to human pharmacokinetics in particular. The most powerful method for assessing similarities between a test substance and a prototypic drug of abuse is the drug discrimination procedure. In contrast to self-administration, drug discrimination is pharmacologically very specific, often reflecting functional activity at receptor level. Dependence is assessed by the occurrence of withdrawal effects on drug discontinuation. Although conceptually simple, interpretation can be complicated by factors such as duration and frequency of administration and observations as well as the choice of end points. Telemetry allows continuous observation of multiple parameters during withdrawal, thereby increasing sensitivity. Presently available tools identify all substances known to cause abuse or dependence, with little risk of false-positives. It remains unclear, however, how predictive these models are with entirely novel substances. Nonetheless, drug abuse/dependence is an area of safety pharmacology where the predictive value of animal models is remarkably high.

Current approaches and issues in non-clinical evaluation of abuse and dependence

Preclinical assessment of drug abuse and dependence has been the subject of several recent regulatory guidelines. Both the European and US authorities recommend a tiered approach and are generally aligned on the methods which should be used. The first tier simply compares the pharmacology of the novel substance to known drugs of abuse. The second tier aims to identify abuse and dependence liability more directly. The most direct approach to assessing reinforcing properties is the i.v. self-administration procedure. Unfortunately there is no standardized procedure for evaluating substances with differing potencies, reinforcement properties or pharmacokinetics (PK). Indeed, the choice of training substance, species and procedural parameters can radically affect the outcome. Apart from the lower cost of the rat, the primate presents several advantages for self-administration studies (potentially greater similarity to humans in behavioral effects, active doses and PK). Although it does not measure abuse liability directly, drug discrimination is a powerful method for assessing the similarity of a test substance to a known drug of abuse. In this procedure an animal uses the interoceptive effects of the substance as the discriminative stimulus to determine which of two responses to make. For certain classes of substance, such as hallucinogens acting via the 5-HT 2A receptor, discrimination is the only procedure currently able to identify them. Drug dependence is assessed by the occurrence of withdrawal effects on drug discontinuation. Although conceptually simple, many factors (duration and frequency of drug treatment, dose/exposure levels, duration of observation after discontinuation) can complicate interpretation. Telemetry may represent a novel approach which allows continuous observation of somatic and behavioral parameters during drug withdrawal thereby increasing sensitivity. Presently available tools can identify essentially all substances known to cause abuse or dependence with little risk of false positives. It remains unclear how effective these models will be with entirely novel substances. Nonetheless, drug abuse/dependence is an area of safety pharmacology where the predictive value of animal models remains very high.

Functional testing in a mouse stroke model induced by occlusion of the distal middle cerebral artery

Reducing post-stroke disability is the major goal of stroke therapy. Consequently, functional testing is essential in experimental stroke studies to increase the predictive value of animal models. We used several sensory and motor tests to assess functional disability in a mouse model of permanent distal middle cerebral artery occlusion (pdMCAO) that induced mainly cortical infarcts. Gait dynamics were transiently disturbed after pdMCAO as measured by different analysis techniques. Stance and brake duration were shorter after pdMCAO. Consistent with sensory and motor deficits the latency to move was prolonged up to 14 days after pdMCAO and the performance in the corner test and handedness were affected on day 1 or 2 after pdMCAO. Heart rate was decreased and heart rate variability were increased after pdMCAO indicating sympathetic–parasympathetic imbalance. In summary, pdMCAO-induced cortical infarcts lead to clinically relevant sensory, motor and cardiac autonomic dysfunction in mice. The present study provides a basis to explore the potential of functional testing for neuroprotection and neuroregeneration after stroke.

Chronic Mouse Model of TMA-Induced Contact Hypersensitivity

Due to the steadily increasing incidence of atopic dermatitis (AD), especially in children, there is a high medical need for new therapies and improved animal models. In mice, trimellitic anhydride (TMA) is routinely used to trigger T-cell-dependent contact hypersensitivity (CHS) reactions. In this study, we compared the standard acute TMA-induced CHS in Balb/c mice with subacute and chronic models of TMA-induced ear inflammation. Compared to the acute model, the chronic CHS model more closely reflects characteristics of AD, such as typical morphological changes of the inflamed skin, strong infiltration with T cells, major histocompatibility complex II-positive cells, eosinophils, and mast cells, a T-helper cell-type (Th) 2 cytokine profile and a strong increase of serum IgE levels. Moreover, a strong lymph node involvement with T-helper cell dominance and a mixed Th1/Th2 T-cell differentiation and activation pattern was demonstrated. Importantly, as demonstrated by successful therapy with prednisolone, the chronic TMA-induced CHS model, in contrast to acute and subacute models, made prolonged therapeutic treatment of a pre-established skin inflammation possible. Altogether, we present an improved model of mouse T-cell-dependent skin inflammation for AD. We hope this model will enhance the predictive value of animal models for therapeutic treatment of atopic eczema.

Predictive value of animal models for human cytochrome P450 (CYP)-mediated metabolism: A comparative study in vitro

One major challenge in drug development is defining of the optimal animal species to serve as a model of metabolism in man. The study compared the hepatic drug metabolism characteristics of humans and six widely used experimental animal species. Classical in vitro model enzyme assays with known human cytochrome P450 (CYP) enzyme selectivity were employed and optimized to target human hepatic CYP forms. The profile of CYP activities best resembling the human was seen in mouse followed by monkey, minipig, and dog liver microsomes, with rats displaying the most divergent. The widest interindividual variability was found in CYP3A-mediated midazolam α-hydroxylase, and omeprazole sulphoxidase activities in human and monkey liver microsomes. These data demonstrate that if hepatic xenobiotic-metabolizing characteristics were to be the sole reason for the selection of animal species for toxicity studies, then the rat might not be the most appropriate model to mimic human CYP activity patterns.

Using objective markers and imaging in the development of novel treatments of chronic pain

Chronic pain is an area of an immense unmetmedical need and pharmaceutical companieshave been putting a lot of effort into developingnew pain treatments. In sp ite of this, attrition inthis area has been high across the industry. Withmost candidates failing in early clinical develop-ment phases, the preclinical–clinical interface isthe most likely reason for the low success rate.Currently, discovery of novel analgesics relies onanimal models of pain; thereby selected candi-dates are then tested in proof-of-concept (PoC)patient trials. However, there are majorconcerns about the predic-tive value of animal models;one much discussed exam-ple being the tachykininNK1 receptor antagonistclass

Strategies for finding new pharmacological targets for neuropathic pain.

Chronic pain of neuropathic origin is an unmet therapeutic challenge that may require the development of novel drug entities. The resources involved in developing novel drugs and testing them in clinical trials are so large that few candidates can be fully tested in practice. A poor choice can have major repercussions. At the same time, the research community has identified large numbers of potential pharmacological targets for analgesia in recent years, with individual investigators promoting favorites with increasing zeal. Because of the uncertain predictive value of animal models of neuropathic pain, it is essential to consider rational strategic approaches to selecting the most likely candidate targets.

Long-term effects of clomethiazole in a model of global ischemia

The failure of neuroprotective drugs in clinical trials has raised questions about the predictive value of animal models. To address this issue we reexamined the efficacy of clomethiazole using functional and histological outcome measures in combination with long-term survival times. Gerbils were exposed to 5 min of global ischemia and received 400 mg/ml clomethiazole (via osmotic minipump) plus a bolus injection (60 mg/kg) 30 min after ischemia. Brain temperature was maintained at ∼36.5°C during ischemia and for the first 30 min after ischemia, and was monitored in all groups for 24 h. Subgroups of clomethiazole-treated gerbils had their temperatures regulated in the normothermic range while in other animals temperature was not controlled. Open-field habituation tests were conducted 5, 10, 30, and 60 days after occlusion. CA1 cell counts and CA1 slice recordings were done at the conclusion of behavioral testing. Clomethiazole significantly attenuated CA1 cell loss at 10-, 30-, and 60-day survival. A modest reduction in habituation deficits was evident only on Day 10 ( P < 0.05). Similarly, field potential amplitude was not maintained in the rostral CA1 region. Clomethiazole produced mild hypothermia that developed over several hours. Based on short-term CA1 cell counts, clomethiazole provided significant histological protection with limited functional preservation. Neuroprotection disappeared when longer survival times (60 day) were employed and temperature confounds eliminated. These data demonstrate the necessity of utilizing more clinically relevant survival times and carefully monitoring/regulating postischemic temperature when assessing potential neuroprotective compounds.

Dietary vitamin A and teratogenic risk: European Teratology Society discussion paper

This review discusses the predictive value of animal models in assessment of possible risk from excess vitamin A consumption during pregnancy and the human evidence concerning risk of congenital malformations from excess vitamin A in the diet, consumed either as a constituent of normal foods or in the form of dietary vitamin supplements. Other sources of exposure to vitamin A include medicines (dermal and oral preparations) and cosmetics, but these are not further considered here. Conservative estimates of the likely safe intake of vitamin A during pregnancy are available, based on results from scientific research to date. However, current uncertainties are such that further research is needed to more clearly define intakes which may be on the borderline between those which are beneficial and those which may pose a risk to the developing embryo and fetus.