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In the 60 years since the publication of The Principles of Humane Experimental Technique , the Three Rs ( Reduction , Refinement , Replacement ) proposed by William Russell and Rex Burch have gradually been accepted throughout the world as ways of facing up to the ethical and scientific dilemmas involved in animal experimentation. However, the scale of animal use and the use of animals as models of humans has continued, seemingly almost unchallenged in much of the scientific community, despite the warnings about models, species differences and human variation spelled out in the The Principles . In this Comment , it is proposed that it is time to move away from the animal welfare focus of the Three Rs, in favour of a wider concept of humanity, which also embraces human welfare. In addition, since less than 10% of new drugs successfully pass from preclinical testing, which is highly reliant on animal procedures, to acceptance for clinical use, it is argued that the aim should not be to directly replace animal testing with non-animal methods with similar aims and which produce similar results, but to take advantage of developments in cell and molecular biology and in computer science, to devise new, different, appropriate, specific and intelligent stand-alone preclinical testing strategies that are applicable to particular human situations.

Background: Even after several decades of human drug development, there remains an absence of published, substantial, comprehensive data to validate the use of animals in preclinical drug testing, and to point to their predictive nature with regard to human safety/toxicity and efficacy. Two recent papers, authored by pharmaceutical industry scientists, added to the few substantive publications that exist. In this brief article, we discuss both these papers, as well as our own series of three papers on the subject, and also various views and criticisms of lobby groups that advocate the animal testing of new drugs., Main Text: We argue that there still remains no published evidence to support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials. In fact, the data in these recent studies, as well as in our own studies, support the contention that tests on rodents, dogs and monkeys provide next to no evidential weight to the probability of there being a lack of human toxicity, when there is no apparent toxicity in the animals., Conclusion: Based on these data, and in particular on this finding, it must be concluded that animal drug tests are therefore not fit for their stated purpose. At the very least, it is now incumbent on-and we very much encourage-the pharmaceutical industry and its regulators to commission, conduct and/or facilitate further independent studies involving the use of substantial proprietary data.

In December 2013, a group of experts produced a report on the management of an animal unit at Imperial College London, following a BUAV investigation that found evidence of systematic failures in the care and monitoring of animals used in procedures there. The Brown Report looked at four areas: the animal welfare and ethical review body (AWERB); the operation of the unit; training; and overall culture. The report made 33 recommendations to improve practices at Imperial College, many of which were relevant to other institutions. In this report, we identify the recommendations that are applicable to all animal facilities, and redraft them as a checklist with supporting information to assist those reviewing their animal care policies. We support the Brown Report's recommendation that institutions should have a vision statement and an action plan, as well as a 'champion' for the Three Rs. We encourage all institutions that use animals to, as a first step, review the performance of their animal units against this checklist., (2014 FRAME.)

In 2013, an undercover investigation by the BUAV raised serious concerns about the use, treatment and care of laboratory animals involved in regulated procedures at Imperial College, London. This led to an inquiry, set up by the college, which found deficiencies in the local ethical review process and a general lack of focus on the implementation of the Three Rs (Replacement, Refinement and Reduction). The Three Rs concept is the foundation of UK and EU legislation, but surveys of the published literature show that lack of its adoption is widespread. In spite of numerous guidelines, publications and publicity material extolling the benefits of the Three Rs to both animals and science, as well as substantial advances in the development, validation, and deployment of mechanistically-based non-animal methods, many scientists prefer to use traditional animal-based approaches. In addition, such scientists tend to pay less attention than they should to strategic planning, experimental design and the choice of appropriate statistical procedures. They are often unaware of the existence of replacement test methods to address all or some of their objectives, and are reluctant to develop and use new replacement methods. We explore some possible reasons for these shortcomings. We summarise the welfare and scientific effects of each of the Three Rs, and argue that: a) there is an urgent need for evidence to be made readily accessible to prospective licensees, which directly demonstrates the beneficial effects on animal welfare of the implementation of the Three Rs, separately and in combination, and the direct link this has with the quality of the scientific data obtained; b) a detailed systematic review of this evidence should be undertaken to augment the inadequate content of the prescribed Module 5 licensee training offered currently in the UK; c) such training (including that suggested in new EU-wide proposals) should be much more comprehensive, with stronger emphasis on the Three Rs, all parts of the syllabus should be fully examined, and there should be no exemptions from Module 5 training; and d) as the responsible Government department in the UK, the Home Office should take measures to tighten up its guidance for local ethical review, and its system of inspection of designated establishments, to obviate the justification for future undercover investigations., (2014 FRAME.)

The scientific basis and advantages of using recently developed CRISPR/Cas-9 technology for transgenesis have been assessed with respect to other production methods, laboratory animal welfare, and the scientific relevance of transgenic models of human diseases in general. As the new technology is straightforward, causes targeted DNA double strand breaks and can result in homozygous changes in a single step, it is more accurate and more efficient than other production methods and speeds up transgenesis. CRISPR/Cas-9 also obviates the use of embryonic stem cells, and is being used to generate transgenic non-human primates (NHPs). While the use of this method reduces the level of animal wastage resulting from the production of each new strain, any long-term contribution to reduction will be offset by the overall increase in the numbers of transgenic animals likely to result from its widespread usage. Likewise, the contribution to refinement of using a more-precise technique, thereby minimising the occurrence of unwanted genetic effects, will be countered by a probable substantial increase in the production of transgenic strains of increasingly sentient species. For ethical and welfare reasons, we believe that the generation of transgenic NHPs should be allowed only in extremely exceptional circumstances. In addition, we present information, which, on both welfare and scientific grounds, leads us to question the current policy of generating ever-more new transgenic models in light of the general failure of many of them, after over two decades of ubiquitous use, to result in significant advances in the understanding and treatment of many key human diseases. Because this unsatisfactory situation is likely to be due to inherent, as well as possibly avoidable, limitations in the transgenic approach to studying disease, which are briefly reviewed, it is concluded that a thorough reappraisal of the rationale for using genetically-altered animals in fundamental research and by the pharmaceutical industry, and for its support by funding bodies, should be undertaken. In the meantime, the use of CRISPR/Cas-9 to generate new transgenic cells in culture is to be guardedly encouraged., (2014 FRAME.)

The latest report on experimental animal use in the EU indicates a slight decrease. However, the figures, which are for 2008, show that around 12 million animals are still used in laboratories throughout Europe. To date, only a summary of the data has been published, and so this report is limited to giving a comparison of trends and significant changes. The impact on the figures of the revision of Directive 86/609/EEC and the 7th Amendment to the Cosmetics Directive 76/768/EEC is discussed. In addition, consideration is given to which areas of research and regulation will need to be closely monitored, and the importance of continuing to push for the implementation of Three Rs initiatives is highlighted., (2010 FRAME.)

At the opening of a meeting to celebrate the 50th anniversary of the publication of The Principles of Humane Experimental Technique, by W.M.S. Russell and R.L. Burch, and the 40th anniversary of the establishment of FRAME, some comments on the early days of the Charity are made, with particular reference to the special contributions made by its founder-Chairman, Dorothy Hegarty, and the author's own appointment as a Trustee, and later as Chairman. Reference is made to some key events and successes, and especially to the importance of FRAME's move from London to Nottingham, and the establishment of an ongoing collaboration with the University of Nottingham, including the setting-up of the FRAME Alternatives Laboratory., (2009 FRAME.)

The objectives of the Fund for the Replacement of Animals in Medical Experiments (FRAME) are spelled out, as laid down in the Charity's Trust Deed of 1969, and the support of the Charity's trustees, consultants, patrons and staff in all that has been achieved during its first 40 years, are recognised. The recent establishment of the W.M.S. and Claire Russell Archive at the University of Nottingham is recognised as a further important link between FRAME and the University., (2009 FRAME.)

A critical analysis is presented of the reports produced by four Technical Expert Working Group Sub-groups (SGs) on Ethical Review, Cost-Benefit, Authorisation and Scope, which were published on the EC website (http://ec.europa.eu/environment/chemicals/lab_animals/ia_info_en.htm), as part of the European Commission (EC)s review of EU Directive 86/609 EEC. This is in addition to our official response to the internet consultation questionnaire, submitted to the Commission on behalf of FRAME. Whilst the respective SG reports were extensive and detailed, we have identified several shortcomings, and in particular, a frequent lack of consensus among the SG members, resulting in a lack of clear guidance for the EC on what the revised Directive should contain, with reference to a number of crucial issues. Such indecisiveness could lead to wide discrepancies in the approaches of the EC, the European Parliament and the EU Member States concerning many issues of importance to animal welfare and the implementation of alternatives to animal experiments. These concerns range from logistical issues, such as requirements for named officers in authorised establishments, and the recording and publishing of statistics on animal use, to ethical and scientific problems, including the use of non-human primates, local ethical review, and education and training on the essential link between the Three Rs concept and best scientific practice. In each case, the basis for our concerns is explained, and suggestions for improvements to be incorporated into the revised Directive are made, in the hope that the harmonisation of approaches to laboratory animal experimentation and the use of alternative methods in the Member States can be maximised.

The Academy of Medical Sciences, the Medical Research Council, the Royal Society and the Wellcome Trust are undertaking a study into the use of non-human primates in biological and medical research. An independent working group of scientific experts, led by Sir David Weatherall, aims to produce a report summarising the findings of this study, early in 2006. The trends in primate research, and the nature and effects of recent and proposed changes in the global use of non-human primates in research, will be investigated. The associated ethical, welfare and regulatory issues, and the role and impact of the Three Rs principles of refinement, reduction and replacement will also be reviewed. As part of this study, a call for evidence was made. The evidence submitted by FRAME emphasised that the use of non-human primates for fundamental research or for regulatory testing still fails to take into account the fact that, although non-human primates are anatomically and physiologically similar to humans, they are not necessarily relevant models for studies on human disease or human physiology. FRAME continues to believe that we have a duty to ensure that these animals are not used without overwhelming evidence that they are the only suitable and relevant models for use in work of undeniable significance.

Personal experiences at FRAME and ECVAM are recalled, alongside the evolutionary progress of the Three Rs (replacement, reduction, refinement,) approach to animal experimentation, described in great decades analogous to the Great Ages of Western Civilisation.

We have assessed each of the OECD Health Effects Test Guidelines (TGs) that were included in an annex to the Internet consultation issued by the European Commission relating to the Registration, Evaluation and Authorisation of Chemicals (REACH) legislation for the testing of new and existing chemical substances. Each guideline has been analysed with respect to its design and its scientific and animal welfare implications, the extent to which it makes use of modern techniques, and its suitability to be used in the REACH system for the testing of large numbers of chemicals. The scientific basis of the test and its justification are considered, as well as the numbers of animals required, and the potential adverse effects on them. The prospects and possibilities for applying the Three Rs (reduction, refinement and replacement) to each of the TGs are also discussed. We have proposed an overall testing strategy for how these TGs and other methods could best be deployed for chemicals testing, should it be necessary to fill data gaps. Certain TGs have been omitted from the strategy, when we have considered them to be unnecessary for chemicals testing. A series of recommendations has been made for improving the TGs with regard to both their scientific content and ways in which they could be better designed in relation to optimising the use of the animals concerned, and minimising adverse welfare consequences to them. Our investigations show that there is an urgent need to update the TGs to reflect modern techniques and methods, and to use current approaches for applying refinement strategies to improve the scientific and animal welfare aspects of the procedures used. Improvements can and should be made in all aspects of toxicity testing, from sample preparation, and animal housing, care and feeding, to dose formulation, test material administration, and the histopathological and clinical analysis of tissue samples. Opportunities for streamlining individual assays are very limited, but testing could be made more efficient by: a) only undertaking studies that provide relevant data; b) making greater use of screens and preliminary testing; c) applying some tests simultaneously to the same animals; d) using one sex; and e) eliminating redundant tests. In conclusion, it is clear that, as they stand, the OECD Health Effects TGs are unsuitable for use in the European Union REACH system, for which potentially very large numbers of laboratory animals will be needed for the testing of a very large number of chemicals.

The background to the establishment of ECVAM in 1991 is summarised, and progress made since 1993 is briefly reviewed in relation to 12 recommendations made at the ECVAM Opening Symposium in 1994 and to statements on tests for chemicals and biologicals endorsed by the ECVAM Scientific Advisory Committee since 1997.

The validation of a test method is the process by which the relevance and reliability of the method are assessed for a particular purpose. It is an essential stage in the evolution of the method from its development to its acceptance and application for regulatory purposes. The principles according to which alternative tests should be validated have been agreed at an international level, although the actual process by which the validation process is conducted varies between different validation authorities. This paper summarises the principles of alternative test development and validation, and describes how the principles have been applied to the validation of in vitro tests by ECVAM.

This commentary comprises our responses to each of the seven conclusions and twenty-four recommendations made in the report of the House of Lords Select Committee on Animals in Scientific Procedures, published in July 2002.

Revolutions in thinking and practice are essential in regulatory toxicology if genuine protection of human beings and the environment is truly to be improved. New test development is the key: Tests should have greater relevance than the current animal procedures based on (1) a mechanistic understanding of the basis of the test method itself and of the toxic phenomenon of concern, (2) taking advantage of new developments in cell and molecular biology and computer systems of various kinds, and (3) a clear understanding of the value of good prediction models. In the not-too-distant future, current research in genomics, proteomics, and metabolomics should provide opportunities for the development of valuable new tests. An inescapable requirement of tests intended to be used for regulatory purposes is validation (i.e., an independent assessment of relevance and reliability for stated purposes according to internationally agreed-upon criteria). However, there is no standard validation scheme; a case-by-case approach is essential. It is important to take advantage of experience, which reveals that prevalidation makes formal validation studies faster, less expensive, and more likely to succeed, and that the procedures for independent assessment used by the European Centre for the Validation of Alternative Methods (ECVAM) and the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) are effective in practice.

A mechanism can be defined as an explanation of an observed phenomenon that explains the processes underlying the phenomenon in terms of events at lower levels of organization. A prerequisite for new, more mechanistic, approaches, which would use in vitro systems rather than conventional animal analogy models, is a strengthening of the underlying scientific basis of toxicity testing. This will require greater recognition of the differences between fidelity and discrimination models and between analogy and correlation models. The development of high-fidelity, high-discrimination tests with a sound mechanistic basis will also require greater appreciation of the interdependence of all the components of test systems and the development of new alternative (i.e., nonanimal) testing strategies that can provide the specific knowledge needed for making relevant and reliable predictions about the potential effects of chemicals and products in human beings. The optimal use of this new knowledge will require fundamental changes to current practices in risk assessment.

The present article represents a consensus view of the appropriate utilization of chimpanzees in AIDS research arrived at as a result of a meeting of a group of scientists involved in AIDS research with chimpanzees and bioethicists. The paper considers which types of studies are scientifically justifiable in this species, the conditions under which such studies should be carried out, and the conditions which should be encouraged for post-experimental retirement of these animals.