Ethics of Research involving animals
Use of animals in current pharmaceutical research and development - continuation II
8.18 Characterisation of vaccines and other biological products during stages 3 and 4 has a number of special features. First, the product may require modification so that it can be administered and remain effective as it is absorbed and transported around the body. Secondly, vaccines commonly contain an adjuvant (e.g. aluminium hydroxide) which is used to increase the effectiveness of the immune response. Both vaccine modification and testing of adjuvants involve the use of animals. The product is often administered to animals and their immune responses are measured by sampling blood and tissue.23 For example, vaccines against tetanus are tested for potency in mice or guinea pigs. Animals are given the tetanus vaccine (which should confer protection) and later receive what would be expected to be a lethal or paralytic dose of tetanus toxin. If the vaccine has the required potency, the toxin will cause no adverse effects for the animals (see also Box 8.5).24 In the past, many more tests were required during which the animals showed symptoms of the disease, which could be severe and even lead to death. This methodology has been replaced in many cases by earlier, more humane, experimental endpoints (see paragraph 5.22), such as changes in weight, body temperature or behaviour.25 In addition, blood and tissue markers of infection are increasingly used.26
8.19 The development of new veterinary medicines often involves studies that use the same species for which the medicine is intended. Usually, animals with specific diseases are used as models, although animals spontaneously affected by the disease or condition are also used in field studies.27 The effect on the animals is specific to the area of research, and may depend also on the state of their health. For example, in the case of the severe respiratory disease pasteurellosis, which affects cattle, 450 calves were used in a programme to develop a vaccine and a significant proportion suffered from the disease.28 The vaccine that was developed has now been used successfully to bring the disease under control.29 In field trials potential suffering is usually avoided by comparing the new vaccine to existing treatments (if available) rather than using placebos as a comparison.
Stage 5: selecting candidate medicines and ensuring their safety
8.20 The aim of stage 5 is to decide whether promising compounds could be tested in trials involving human volunteers. Questions that need to be addressed include:
- Do particular compounds meet the quality threshold to be a successful medicine?
- Would the medicine be safe and effective for humans?
- How best could the medicine be administered?
- How much of the medicine will be active in the body?
- Is it possible to produce enough of the active compound at an acceptable cost?
8.21 Once a candidate drug has been selected, toxicity studies are then conducted on animals, completing the pre-clinical phase of the development process.30 The increased knowledge gained in the earlier stages of the modern drug-discovery process means that potential medicines are now better characterised by the time that the toxicity studies begin. Extrapolations are made from animal and non-animal data to predict safety and the initial dose of medicines to be used in humans. The use of toxicity databases, toxicogenomics, proteomics and high-throughput screening (see paragraph 8.6) play an important role in providing additional information and helping to reduce the use of traditional toxicity studies. Together with data from non-animal studies, pre-clinical results of these tests are submitted to regulatory authorities in the application for permission to conduct clinical studies in human volunteers. The final outcome of this stage is a candidate drug that meets the safety criteria set by regulatory bodies and has the potential to be developed into a successful and commercially viable product.
Use of animals
8.22 At this, and subsequent stages, toxicity tests on animals are undertaken to meet the requirements of regulators that a potential medicine demonstrates an acceptable balance of safety and efficacy (see paragraphs 9.6–9.21). The custom and practice of regulatory agencies has been to rely on data from animal research when making these judgements, although increasingly more data from validated non-animal methods are generated and accepted. Toxicity studies account for between five and 20 percent of animal use by the pharmaceutical industries. In 2003, pharmacological safety and efficacy evaluation constituted ten percent of the total number of animal procedures in Great Britain.31 Animal tests at this stage are much more uniform compared to the experiments carried out in drug discovery and they need to be conducted in a format that is accepted worldwide. Some of the most important tests, and associated welfare implications, are described in Chapter 9, in which we discuss toxicity testing in more detail. (The scope of Refinements,32 and the application of the Three Rs in toxicity testing more generally, are considered in Chapters 11 and 12).
Vaccines and veterinary medicines
8.23 Before administering a novel vaccine to human volunteers researchers need to ensure that the candidate vaccines will not infect trial participants with the disease (as might be possible with live vaccines) or lead to an inappropriate immune response, such as producing antibodies that have adverse effects. It also needs to be ascertained whether the agent, or additives such as adjuvants, are likely to cause direct irritation at the site of application. The common types of test required are single- and repeated-dose toxicity assessments and testing to determine any local irritation (see paragraphs 9–9-9.18).33 Specific tests are also required to determine how effective the vaccine is in protecting animals against challenge with the pathogen. In order to assess efficacy, the test vaccine is administered to animals and the disease is subsequently induced. If the vaccine does not protect the animals they may experience pain or suffering related to the disease, although humane endpoints are usually chosen. Animals are euthanised when these are reached.
8.24 Veterinary medicines are generally evaluated for safety using the species in which they will eventually be used (see paragraph 8.19).
Footnotes23 Leenaars PPAM, Hendriksen CFM, de Leeuw WA et al. (1999) The production of polyclonal antibodies in laboratory animals
ECVAM Workshop Report 35 ATLA 27: 79–102.
24 See Weisser K and Hechler U (1997) Animal Welfare Aspects in the Quality Control of Immunobiologicals: A critical
evaluation of animal tests in pharmacopoeial monographs (Nottingham: FRAME, ECVAM and the Paul Ehrlich Institut).
25 See Hendriksen CFM and Morton DB (Editors) (1999) Humane Endpoints in Animal Experiments for Biomedical Research
Proceedings of the International Conference, 22–25 Nov 1998, Zeist, The Netherlands (London: Royal Society of Medicine),
available at: http://www.lal.org.uk/endpoints1.html. Accessed on: 26 Apr 2005.
26 Griffin JF (2002) A strategic approach to vaccine development: animal models, monitoring vaccine efficacy, formulation and
delivery Adv Drug Deliv Rev 54: 851–61.
27 This is regulated under the authority of Animal Test Certificates (ATC). See Veterinary Medicines Directorate (2004) Animal
Test Certificates, available at: http://www.vmd.gov.uk/lu/amelia/amelia13n.pdf. Accessed on: 26 Apr 2005.
28 This would have included the animals used as the positive controls (to prove the bacteria could cause the disease) and unprotected animals that had been administered trial vaccines that proved ineffective.
29 National Office of Animal Health (2002) Vaccination of farm animals, available at:
http://www.noah.co.uk/issues/briefingdoc/22-vaccfarmanimals.htm. Accessed on: 3 May 2005.
30 The pre-clinical phases (discovery, selection and characterisation of promising candidate medicines and toxicity studies) take on average four to five years to perform, and cost on average £200 million. See Network Science (2004) The Process of Drug
Development, available at: http://www.netsci.org/scgi-bin/Courseware/projector.pl?Course_num=course1&Filename=top.html.
Accessed on: 26 Apr 2005.
31 Eighty-three percent of toxicological procedures were performed to comply with legislative or regulatory requirements. See Home Office (2004) Statistics of Scientific Procedures on Living Animals Great Britain 2003 (London: HMSO).
32 Refinements can be implemented through the use of more sensitive markers of toxicity (for example, blood tests or remote monitoring) and more humane endpoints. See Organisation for Economic Co-operation and Development (2000) Guidance
Document on the Recognition, Assessment, and Use of Clinical Signs as Humane Endpoints for Experimental Animals Used in Safety Evaluation, available at:
http://www.olis.oecd.org/olis/2000doc.nsf/4f7adc214b91a685c12569fa005d0ee7/c125692700623b74c12569bb005aa3d5/$FILE/0
0087372.PDF. Accessed on: 26 Apr 2005.