Pharmacogenetics
The impact of pharmacogenetics
3.3 The application of pharmacogenetics to the development of new medicines and other products such as vaccines has implications for the way in which basic research and clinical trials are designed and managed, and for the cost of undertaking clinical trials.1
Pharmacogenetics may be of relevance at various stages in the development of new medicines. The first stage, basic research, involves studying the biological mechanisms that contribute to the pathogenesis of a particular disease or whose modulation may alleviate its signs and symptoms. This may enable researchers to determine the main steps in the disease process and to identify likely targets for medicines. Pharmacogenetics could be of use in understanding features of diseases that may direct treatment, as in the case of Herceptin (Box 2.3: Case study 2). The next stage involves identifying compounds that may be suitable as medicines. Many compounds will be identified, and pharmacogenetics may sometimes be helpful in eliminating those that are unlikely to be effective in large groups of people.
3.4 Compounds that have been selected for further study are then tested in the laboratory and on animals. Those which seem promising may then be tested in human subjects to determine their safety and efficacy (see Box 3.1). If some individuals show little response to treatment, this does not prevent the development of the medicine, provided that there is a significant benefit in health to the group as a whole. In contrast, adverse reactions in a minority of participants in a clinical trial may sometimes mean that the medicine does not receive regulatory approval.2
The application of pharmacogenetic analysis could, in some cases, identify those individuals participating in research who are less likely to respond or who are at risk of adverse reactions, especially in Phases II and III. These individuals could then be excluded from the trials. This could lead to better protection of participants.3
Moreover, the medicines could then be considered for a specific, though possibly small, subgroup of the patients rather than the larger group for whom the medicine was originally intended. However, pharmacogenetic analysis may not be applicable to all clinical trials, and the benefits outlined above may be tempered by other effects of stratifying patients (see paragraphs 4.27 – 4.47).
1 Although the focus of this Report is on the use of pharmacogenetics in connection with the treatment of disease, it should be noted that there is the potential to apply this technology to public vaccination programmes for the prevention of disease, where the vaccine in question is harmful for a small subpopulation that could be identified by genetic means. The ethical case for applying pharmacogenetics in such cases would be particularly strong, since those who are vaccinated are typically healthy children, and such vaccines are given not only for the benefit of the individual but for the general population. Under these circumstances there may be exceptional moral pressure to minimise the risk of harm to the individual being treated. However, given the very low probability of complications and the economic constraints on programmes of vaccination, such a screening test would need to be both extremely effective and inexpensive.
2 Clinical trials require the approval of independent local or regional ethics review committees, which assess whether the trial will contribute to the improved treatment of the condition in question, and ensure that systems are in place for securing informed consent from participants, for monitoring their condition, and for enabling them to withdraw from the study if they wish. There is considerable guidance on the ethics of research on human subjects, including the following: World Medical Association (as amended 2000) Declaration of Helsinki; International Conference on Harmonisation (1997) Note for Guidance on Good Clinical Practice; MRC (1998) Guidelines for Good Clinical Practice in Clinical Trials; The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1979) The Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects of Research; National Bioethics Advisory Commission (2001) Ethical and Policy Issues in Research Involving Human Participants.
3 The SNP Consortium Ltd. Genotyping technology products user requirements survey. White Paper obtained through SNP Consortium (2000) Better Medicine through Genetics Hinges on Public Acceptance. Available: http://snp.cshl.org/news/ medicine.shtml. Accessed on: 25 Feb 2002.