EU Directive Response

Q8 Do you have any comments on the provisions of Article 4 relating to replacement, reduction & refinement?

We are concerned that although Article 4 requires that animal use is not authorised where alternative methods of testing exist which do not involve animal use, it is difficult to ensure, without enlisting relevant expertise in each case, that all of the options have been exhausted. An expert in in vitro technologies, ideally from an external body to the institute conducting the research, should always be consulted before a research proposal is approved. This would help to ensure that methods more relevant to humans are not overlooked because the applicant is not aware of them.

We disagree that replacement alternatives should be limited to those “reasonably & practically available” as this is difficult to define objectively, and may be sacrificed to convenience if not cost. Moreover, the more widespread the use of these technologies becomes, the faster their cost will decrease & the easier it will become to obtain the relevant materials & to use the most relevant human biology-based methods.

We are also concerned that the use of new technologies, even for drug safety testing, ought not to be limited to those which have already been internationally validated. The more these technologies are used & subjected to peer review, the faster their use will spread & the more improvements will be introduced. Furthermore, the burden of validation is unfairly shouldered only by new techniques, while the animal tests they seek to replace have never been subjected to such rigorous analysis. Our concern is that animal tests, rather than being assumed to be useful, ought also to be subjected to rigorous validation procedures.

Replacement ought to be encouraged above reduction and refinement, as there is increasing evidence to suggest that the human biology-based technologies now available are making the use of animal tests, which will always be subject to uncertainties when attempting to extrapolate to humans, redundant. Whilst reduction and refinement may bring animal welfare benefits, as a patient safety organisation, we are concerned with the predictivity of any technique.

Q12 & 13 What are your views on the provisions relating to Great apes?

The use of Great apes does not appear to contribute in any significant way to the body of data which can be safely applied to people, and so we approve of the ban.

Q47 Do you have any comments on the provisions for retrospective assessment of projects? Or our belief that further clarification is required?

We agree that retrospective assessment of projects is essential. Without retrospective analysis, it is impossible to determine whether the anticipated benefits of the research, which formed the basis of the projects’ approval, were realised. If the projected benefits do not accrue, this would be good grounds for declining to allow such research, or similar, to continue. Additionally, it would be beneficial if such assessments were made public, or at least made available to other bodies which might be called upon to judge similar applications. This could reduce duplication of research unlikely to benefit humankind. The publication bias in favour of positive research is well documented, and making the outcomes of retrospective assessments public would also provide an invaluable antidote to this bias. We do not believe that the projects’ investigators should be responsible for evaluating whether their projects’ objectives were achieved, as it would be difficult to guarantee the objectivity of the assessment.

Q54 Do you have any comments on the provisions to encourage the development of alternative approaches?

Although we applaud every effort to encourage the development of non-animal approaches, we would like to see an independent assessment of the current state of technology. There are numerous advanced technologies already in place which take advantage of left over human tissues, biopsies, computer models, genetic technologies, non-invasive imaging & safe ultra-low dose first-in-man studies using microdosing and microdialysis.

We are particularly interested to determine whether drug safety testing could be improved, by conducting an independent scientific comparison between a system of human biology-based methods and the animal-based tests currently required. This could be achieved by testing a panel of drugs for which both human and animal data are already available in a battery of human biology-based assays. The three data sets could then be compared to see whether the human biology-based assays identified more of the effects of drugs in humans than were identified by the animal tests. 250 MPs supported this idea in an Early Day Motion (Animal testing of drugs) in 2006. The comparison is the subject of the Safety of Medicines (Evaluation) Bill 2009.

Q62 Do you have any views on the proposal for review of the directive?

We support article 53, which proposes that the Directive ought to be reviewed 10 years after implementation. We agree that regular thematic reviews would be of huge benefit, and are particularly anxious to see independent assessments of the ability of animal research to deliver the benefits it is supposed to, especially as compared to the ability of current and upcoming human biology-based methods to do so.

Q under line 166: Can you suggest how we might estimate the monetary value of the potential benefits to science, welfare, transparency & harmonization of the provisions relating to animal welfare & alternatives? Can you suggest any sources of evidence to enable such an estimate to be made?
Switching to human biology-based methods would be very beneficial in terms of time, cost and above all, effectiveness, particularly with regard to drug safety testing. According to the US Food and Drug Administration (White Paper, Innovation or Stagnation, 2004), 92% of all new drugs which enter clinical trials fail, the majority due to problems with safety or efficacy. Di Masi et al (Journal of Health Economics 22 (2003) 151–185) estimate that even a very modest improvement in efficiency of a few percent would translate into savings of millions of pounds – savings which could be passed on to healthcare providers.
The extremely high failure rates of drugs in clinical trials, which are very expensive and time-consuming to run, is a major reason for the high cost of new drugs. The total cost of preclinical animal trials has been estimated to be €2.29-6million (or almost £2-5million). Many human biology-based methods not only provide more species-relevant information than the animal tests they would replace; they are also orders of magnitude faster and cheaper. By facilitating optimal drug candidate selection as early as possible in the drug development process, the implementation of human cell-based technologies could significantly reduce drug development time, costs and animal use by reducing the number of compounds which make it through to further testing (Tsaioun et al, BMC Neurology 2009, 9(Suppl 1):S1).

The importance of moving away from the traditional reliance on animal-based toxicology was recognised in a report commissioned by the US Environmental Protection Agency (Toxicity Testing in the 21st Century: A Vision and a Strategy (2007)), which recommended that the current animal-based testing system be replaced with faster and cheaper technologies which also provide data “more directly relevant to human exposures.” In order to bring about this visionary switch, the National Human Genome Research Institute, the US EPA and the US National Toxicology Program have launched a collaboration, the details of which were outlined early the following year (Collins et al, Science, 319, 906-907).

An International Business Machine (IBM) Report, Pharma 2010, published in 2004, estimated that adopting the latest technologies in computer-based technology alone could reduce drug development times from 12-14 years to 3-5 years, and cut costs by three quarters to $200 million per new drug.

A Cambridge Health Institute report (also quoted by Robert Goldberg, USA Today, 28 Feb 2005: http://www.usatoday.com/news/opinion/editorials/2005-02-28-edit-fda_x.htm) estimated that healthcare providers and consumers could save $100 billion per year if ADRs were eliminated, a figure which does not take into account the emotional and social burden of unnecessary illness, or the economic cost of lost productivity due to work absence.