Poorly predictive animal models of disease cause avoidable suffering and hamper the discovery of new treatments for patients. A focus on
mechanistic modelling has the potential to reduce animal suffering as well as improving translation from the bench to the bedside.
The Alliance is an exciting new collaboration, founded to address an urgent need to drive research and development, policymaking, awareness, outreach, and education into human-based methods of safety testing and biomedical research
Animals are still widely used in drug development and safety tests, despite evidence for their lack of predictive value. In this regard, we recently showed, by producing Likelihood Ratios (LRs) for an extensive data set of over 3,000 drugs with both animal and human data, that the absence of toxicity in animals provides little or virtually no evidential weight that adverse drug reactions will also be absent in humans. While our analyses suggest that the presence of toxicity in one species may sometimes add evidential weight for risk of toxicity in another, the LRs are extremely inconsistent, varying substantially for different classes of drugs. Here, we present further data from analyses of other species pairs, including nonhuman primates (NHPs), which support our previous conclusions, and also show in particular that test results inferring an absence of toxicity in one species provide no evidential weight with regard to toxicity in any other species, even when data from NHPs and humans are compared. Our results for species including humans, NHPs, dogs, mice, rabbits, and rats, have major implications for the value of animal tests in predicting human toxicity, and demand that human-focused alternative methods are adopted in their place as a matter of urgency.
Animal use continues to be central to preclinical drug development, in spite of a lack of its demonstrable validity. The current nadir of new drug approvals and the drying-up of pipelines may be a direct consequence of this. To estimate the evidential weight given by animal data to the probability that a new drug may be toxic to humans, we have calculated Likelihood Ratios (LRs) for an extensive data set of 2,366 drugs, for which both animal and human data are available, including tissue-level effects and MedDRA Level 1–4 biomedical observations. This was done for three preclinical species (rat, mouse and rabbit), to augment our previously-published analysis of canine data. In common with our dog analysis, the resulting LRs show: a) that the absence of toxicity in the animal provides little or virtually no evidential weight that adverse drug reactions (ADRs) will also be absent in humans; and b) that, while the presence of toxicity in these species can add considerable evidential weight for human risk, the LRs are extremely inconsistent, varying by over two orders of magnitude for different classes of compounds and their effects. Therefore, our results for these additional preclinical species have important implications for their use in predicting human toxicity, and suggest that alternative methods are urgently required.
The application of the Integrated Discrete Multiple Organ Co-culture (IdMOC®) system in the evaluation of organ-specific toxicity is reviewed. In vitro approaches to predict in vivo toxicity have met with limited success, mainly because of the complexity of in vivo toxic responses. In vivo properties that are not well-represented in vitro include organ-specific responses, multiple organ metabolism, and multiple organ interactions. The IdMOC system has been developed to address these deficiencies. The system uses a ‘wells-within-a-well’ concept for the co-culturing of cells or tissue slices from different organs as physically separated (discrete) entities in the small inner wells. These inner wells are nevertheless interconnected (integrated) by overlying culture medium in the large outer containing well. The IdMOC system thereby models the in vivo situation, in which multiple organs are physically separated but interconnected by the systemic circulation, permitting multiple organ interactions. The IdMOC system, with either cells or tissue slices from multiple organs, can be used to evaluate cell type-specific or organ-specific toxicity.
Dogs remain the main non-rodent species in preclinical drug development. Despite the current dearth of new drug approvals and meagre pipelines, this continues, with little supportive evidence of its value or necessity. To estimate the evidential weight provided by canine data to the probability that a new drug may be toxic to humans, we have calculated Likelihood Ratios (LRs) for an extensive dataset of 2,366 drugs with both animal and human data, including tissue-level effects and Medical Dictionary for Regulatory Activities (MedDRA) Level 1–4 biomedical observations. The resulting LRs show that the absence of toxicity in dogs provides virtually no evidence that adverse drug reactions (ADRs) will also be absent in humans. While the LRs suggest that the presence of toxic effects in dogs can provide considerable evidential weight for a risk of potential ADRs in humans, this is highly inconsistent, varying by over two orders of magnitude for different classes of compounds and their effects. Our results therefore have important implications for the value of the dog in predicting human toxicity, and suggest that alternative methods are urgently required.
This paper is an overview of the applications of the technique of Accelerator Mass Spectrometry (AMS) in the biomedical drug development field. The work described here has been carried out at Xceleron (York, UK and Germantown, MD, USA), and it aims to apply AMS to provide better information about the human pharmacokinetic/metabolic behaviour of drugs or drug candidates as early as possible. It is hoped that the use of this technique will contribute to the delivery of better, more effective drugs onto the market sooner, which will be good news for all concerned.
The pharmaceutical industry is failing in its primary function, with increasing expenditure and decreased output in terms of new medicines brought to market. It cannot carry on as it is, without sliding into a terminal decline. It must, therefore, take some positive steps toward addressing its problems. We do not have to look far to see one very obvious problem, namely, the industry’s continuing reliance on nonhuman biology as the basis of its evaluation of potential safety and efficacy. The time has come to focus on the relevant, and to realise that more human-based testing is essential, if the industry is to survive as a source of innovation in drug therapy. This can incorporate earlier clinical testing, in the form of microdosing, and promotion of the development of more-powerful computational approaches based on human information. Fortunately, headway is being made in both approaches. However, a problem remains in the lack of functional evaluation of human tissues, where the lack of commitment, and the inadequacy of the tissue resource itself, are hampering any serious developments. An outline of a collaborative scheme is proposed, that will address this issue, central to which is improved access to research tissues from heart-beating organ donors.
Drug development currently depends on animal models to provide an accurate prediction of human physiology and pathophysiology. However, as is clear from clinical trial failures during phases II and III, such in vivo models do not always predict the effects that a drug can elicit in humans. Tests with human tissues, which are obviously considered to be the closest model of human in vivo function, could fill the gap between animal-based tests and trials in patients. Despite clear advantages, logistical and ethical barriers prevent fresh human tissues from being widely used during drug development. Biopta is aiming to make human tissue testing a regular element of drug development, and works to lower the barriers surrounding the availability of tissue and practicalities of experimental work.
Animal models are still widely used to assess the efficacy or safety of new pharmaceutical products. Since their limitations in predicting actions of drugs in humans are becoming more and more apparent, there is an urgent need to revisit the use of animals in pharmaceutical research. Herein, we review how the Innovative Medicines Initiative (IMI), the largest public–private partnership in the life sciences, is reducing, refining and replacing the use of animals in the context of its global mission, namely, to boost research and the development of new medicines across the European Union.