Ethics of Research involving animals
Support for the marketed medicine
8.33 Once a medicine is approved by the regulatory agencies, Phase IV clinical trials monitor longterm effects in large numbers of patients and evaluate economic aspects of the medicine. Extensive programmes to capture information on disease epidemiology and the outcomes of using the medicine may be established. This information gathering may also include sampling, for example to obtain pharmacogenetic data, to inform the very first stages of drug discovery. New indications and new formulations are also closely examined. Medicines originally intended for treatment of one disease are sometimes found to have beneficial effects for others (see Boxes 8.3 and 8.4).
| Box 8.3: Testing approved drugs for a novel use: example of animal research undertaken after a medicine is on the market Fox A, Gentry C, Patel S, Kesingland A and Bevan S (2003) Comparative activity of the anti-convulsants oxcarbazepine, carbamazepine, lamotrigine and gabapentin in a model of neuropathic pain in the rat and guinea pig Pain 105: 355–62.* The aim of this research was to find out whether drugs that are currently used to treat epilepsy could also be effective as pain killers for persistent neuropathic pain. This form of pain is produced by the nervous system itself, ‘phantom’ limb pain in amputees being one extreme example. Clinical management of neuropathic pain is very difficult as it responds poorly to opiates and non-steroidal anti-inflammatory medicines. It is treated primarily with anti-epileptic medicines and anti-depressants, although both are associated with significant use-limiting adverse effects. The researchers concluded from their experiments on guinea pigs and rats that some of the anti-epileptic medicines administered were able to relieve neuropathic pain, although the effects differed between the two species. These new medicines were not accompanied by the use-limiting side effects exhibited by current treatments for neuropathic conditions. In some animal models for neuropathic pain, the spinal or facial nerves of the animal have been fused, leading to the development of a long-lasting pain response. In this example, guinea pigs and rats had the sciatic nerve in one leg surgically exposed, and one third to one half of its thickness was tied with a suture under anaesthetic. The aim of this intervention was to reproduce the exacerbated response that sufferers from neuropathic pain experience in response to a normally mild stimulus. The animals were allowed to recover for approximately two weeks after surgery. Post-operative painkillers were not used since the development of pain was the object of the study. Following recovery, the researchers assessed the pain response by applying increasing pressure to the paws of the animals. The threshold at which the animal flinched was measured for both the injured and the uninjured hind paw after which greater pressure was not applied. The medicine under test was then administered and the same procedure was carried out for up to six hours thereafter, and repeated for up to six days. A further experiment was carried out on rats to measure the pain response to a stimulus that would not usually cause pain. Thin filaments were applied to both hind paws, starting with a low force. This was repeated five times at intervals of one or two seconds and the response noted. The researchers waited for at least five minutes between using successively stiffer filaments. The filament force that produced a withdrawal of the paw was denoted as the threshold for the stimulus, after which greater pressure was not applied. Thresholds were determined prior to and up to six hours following drug administration. All animals showed an increased sensitivity to pain following the surgical procedure. * This is an example of animal research that has been carried out in the UK and published in a peer-reviewed journal. Details relate to this specific example and should not be taken to represent a ‘typical’ animal experiment. It is important to note that individually published experiments usually form one part of a continuing area of research, and the significance of the results may therefore be difficult to interpret. |
| Box 8.4: Use of thalidomide Thalidomide is a notorious example of the failure of methodology in pharmaceutical research.* The example is frequently used to argue that the results of animal studies cannot be applied to humans. Thalidomide was licensed as a sedative after safety tests performed on animals were approved by the regulatory authorities. Between 1957 and 1961 it was prescribed to pregnant women as a treatment for morning sickness and other symptoms. In December 1961 The Lancet published a letter by Dr W.G. McBride, an Australian obstetrician, stating that he had observed frequent limb deformities in babies of women who had taken thalidomide during pregnancy. It later emerged that more than 10,000 children around the world had been affected.† Research published five months after Dr McBride’s letter confirmed that thalidomide given to pregnant rabbits resulted in the birth of litters with similar limb deformities to those in humans. Subsequent research showed that offspring of mice, rats, hamsters, macaques, marmosets, baboons and rhesus monkeys suffered comparable effects. Although the licensing of thalidomide involved animal research, tests on pregnant animals were not undertaken as this was not a legal requirement. Partly in response to the thalidomide tragedy, the UK passed the Medicines Act of 1968, which regulates the testing and supply of medicines in the UK (see paragraph 13.49).‡ Strict measures have been put in place in many countries to prevent the use of thalidomide by pregnant women. At the same time, the drug has been found to be an effective treatment for other conditions. Celgene Corporation has begun developing the medicine for a range of potential indications, including AIDS-related, dermatological and cancer-related conditions.∫ In 1998 the US Food and Drug Administration granted marketing clearance to Celgene’s Thalomid for the treatment of erythema nodosum leprosum (ENL), a severe and debilitating condition associated with leprosy (Hansen’s disease). The Authority also imposed unprecedented restrictions on the distribution of the medicine. These included restriction on those who were permitted to prescribe thalidomide, a requirement for a negative pregnancy test result within 24 hours of starting therapy and weekly testing during the first month of use. Women were also required to use two reliable forms of contraception simultaneously while taking the drug.** * See RDS Thalidomide, available at: http://www.rdsonline. org.uk/pages/page.asp?i_ToolbarID=5&i_PageID=1070 . Accessed on: 2 May 2005. † Powell RJ (1996) New roles for thalidomide BMJ 313: 377–8. ‡ ABPI Law - Approval of medicines, available at: http://www.abpi.org.uk/amric/basic5.asp. Accessed on: 2 May 2005. ∫ See Celgene Thalomid, available at: http://www.celgene.com/Products.aspx?s=1. Accessed on: 21 April 2005; see also Pollard M (1996) Thalidomide promotes metastasis of prostate adenocarcinoma cells (palii) in L-W rats. Cancer Lett 101: 21-4 **Food and Drug Administration (1998) FDA approves thalidomide for Hansen’s disease side effect, imposes unprecedented restrictions on distribution, available at: http://www.fda.gov/bbs/topics/answers/ans00887.html. Accessed on: 2 May 2005. |