Safer Medicines - putting patient safety first

Putting patient safety first

European Molecular Biology Organization 01/09/07

Comment on The ethics of animal research by Festing & Wilkinson

Simon Festing and Robin Wilkinson’s scientific defence of animal research rests on their claim that the development of new medicines and treatments is “all made possible by animal research” (Festing & Wilkinson, 2007). Yet the Advertising Standards Authority (ASA; London, UK) has ruled that such claims are misleading (ASA, 2005).Europeans for Medical Progress (EMP; London, UK) is an independent organization dedicated to the safety of patients. Our concern is that patients are endangered by an unwarranted reliance on results from animal models that have not been validated and are frequently misleading. We seek unprecedented scientific scrutiny of animal tests to predict drug safety—the track record of which is abysmal. Our aim is to ensure that biomedical research practices are rigorously evidence-based. However, the results of evidence-based medicine often conflict with the agenda of special interest groups (Dickersin et al, 2007).

We wonder why the Research Defence Society (RDS; London, UK) opposes an independent comparison of animal tests with the latest human-based tests for drug safety, and why they have even lobbied members of the British Parliament (MPs) not to support EMP’s initiative. Surely, all sides should agree that an evaluation of the scientific strengths of animal-based testing of drugs is a positive exercise? However, no independent comparison of the relative efficacy of animalcompared with human-based methods has ever been attempted. All four enquiries mentioned by Festing & Wilkinson in their Talking Point (Festing & Wilkinson, 2007) concluded that reviews of the reliability and relevance of animal research are necessary. The House of Lords Select Committee report concluded this was “a matter of urgency” (UK, 2002).

The report further acknowledged that, “all sides of the debate on animal procedures say that animals are highly imperfect models. It will be for the benefit of science, and ultimately of human health, if better methods of research and testing could be developed.” Festing & Wilkinson also did not acknowledge the failings of animal research, such as the fact that 92% of new drugs fail in clinical trials, even following success in animal tests (FDA, 2004), as dramatically illustrated by the recent TG N1412 trial. Approximately 150 stroke treatments that were successful in animals have failed in clinical trials (www.camarades.info), sometimes injuring or killing patients, for example Aptiganel (Birmingham, 2002).

Vioxx® (Merck, Whitehouse Station, NJ, USA) caused hundreds of thousands of heart attacks and strokes despite animal testing indicating that it was cardioprotective (Topol, 2004). How much more evidence of failure is needed before we consider directly assessing the worth of animal tests relative to the latest tests that are now available? In January 2007, a systematic study in the British Medical Journal based on six reviews found that animal tests accurately predict human response less than 50% of the time (Perel et al, 2007). A study of the translation of animal research into human treatments cautioned those who conduct clinical research to expect “poor replication of even high-quality animal studies” (Hackam & Redelmeier, 2006).

Festing & Wilkinson highlighted the difficulty of mimicking a whole living system; however, the answer is unlikely to be found in studying the wrong system: “[A] relative lack of severe toxicity in animal models should never be construed as a guarantee of safety in man, as the story of thalidomide taught us” (Goodyear, 2006). This is where technologies such as microfluidics and, in particular, microdosing, come into their own. Festing & Wilkinson’s criticisms of microdosing are unsupportable. By 2010, 90% of pharmaceutical companies plan to use microdosing (Wilkinson, 2007), and the European Medicines Agency (EMEA; London, UK) and the US Food and Drug Administration (FDA; Rockville, MD, USA) support its use to reduce the time, cost and risks associated with developing new drugs (EMEA, 2004; FDA, 2006).

In the light of so much evidence of the hazards posed by misleading animal data, unsubstantiated claims that Festing & Wilkinson make in their Talking Point, such as, “[t]he benefits of animal research have been enormous”, are an inadequate form of justification. In addition, stating that, “it would have severe consequences for public health and medical research if it were abandoned” does not withstand scrutiny in the face of promising advances such as microdosing, microfluidics, virtual organs and virtual clinical trials. UK Biobank (Stockport, Cheshire, UK) promises to build substantially on an exciting breakthrough just announced by The Wellcome Trust (London, UK). The identification of many new genes implicated in serious, common diseases was only made possible by the analysis of DNA from thousands of patients and volunteers (Todd et al, 2007).

Medical progress depends on a continued focus on humans and their varying susceptibility to diseases and drugs. Now that we have the technology to design and test drugs specifically for humans, what is the value of animal tests? Cancer Research UK (London, UK) acknowledges that “We do trials in people because animal models do not predict what will happen in humans” (Burtles, 2006).

It seems that the public remains to be convinced about the merits of animal testing. In a 2006 Sky News poll—which dwarfed the surveys quoted by Festing & Wilkinson—52% of almost one million people said they were not in favour of testing on animals (news.sky.com/skynews/ polls/displayresults/1,,91153-1003444- 2,00.html). Our own survey of GP s revealed that only 21% would have more confidence in animal tests for new drugs than in a battery of human-based safety tests, and that 83% would support an independent scientific evaluation of the clinical relevance of animal experimentation; figures which the polling company has never disputed (www. safermedicines.org). Furthermore, a majority of MPs also support an independent scientific evaluation of the use of animals as surrogate humans in drug safety testing and medical research (Hancock, 2006). It seems that provivisectionists are alone in opposing scientific scrutiny of the controversial practice they defend.

REFERENCES

ASA (2005) Non-Broadcast Adjudications: Association of Medical Research Charities. London, UK: Advertising Standards Authority

Birmingham K (2002) Future of neuroprotective drugs in doubt. Nature Med 8: 5

Burtles S (2006) Report of the Expert Scientific Group on Phase One Clinical Trials. London, UK: Cancer Research UK

Dickersin K, Straus SE, Bero LA (2007) Evidence based medicine: increasing, not dictating, choice. BMJ 6: s10

EMEA (2004) Position Paper on Non-Clinical Safety Studies to Support Clinical Trials with a Single Microdose. London, UK: European Medicines Agency

FDA (2004) Innovation or Stagnation, Challenge and Opportunity on the Critical Path to New Medical Products. Rockville, MD, USA: Food and Drug Administration

FDA (2006) Guidance for Industry, Investigators, and Reviewers. Exploratory IND Studies. Rockville, MD, USA: Food and Drug Administration

Festing S, Wilkinson R (2007) The ethics of animal research. EMBO Rep 8: 526–530

Goodyear M (2006) Learning from the TGN1412 trial. BMJ 25: 677–678

Hackam DG, Redelmeier DA (2006) Translation of research evidence from animals to humans.JAMA 296: 1731–1732

Hancock M (2006) Early Day Motion: Animal Testing of Drugs. London, UK: Parliamentary Information Management Services

Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, Mignini LE, Jayaram P, Khan KS (2007) Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 27: 197–200

Todd JA et al (2007) Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Gen 39: 857–864

Topol EJ (2004) Failing the public health— Rofecoxib, Merck, and the FDA. N Engl J Med 351: 1707–1709 UK (2002)

House of Lords Select Committee on Animals in Scientific Procedures, Volume I— Report. London, UK: The Stationery Office

Wilkinson M (2007) Xceleron to accelerate growth further. Online article published on http://www.drugresearcher.com, 3 May. Montpellier, France: Decision News Media

Kathy Archibald is Director of Europeans for Medical Progress; Margaret Clotworthy+ is Science Consultant for Europeans for Medical Progress Trust. +E-mail: margaret.clotworthy@ntlworld.com
doi:10.1038/sj.embor.7401057

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