Pharmacogenetics
Stratification and the development of new medicines
21 Genetics may influence choice of medicine in several different ways. People are known to differ in the genetic variants they possess of a series of enzymes concerned with the absorption, metabolism and excretion of medicines (see Box 2.1). These are characteristics with which a person is born. They do not necessarily influence susceptibility to disease, but rather the way the individual body processes medicines to which it is exposed. They often affect classes of medicines rather than specific individual medicines (see Box 2.2, Case study 1). People with particular genotypes may find some medicines ineffective, or may need higher or lower doses in order to achieve a therapeutic effect because they break the substances down either more or less rapidly. There are a large but finite number of these systems for processing medicines, and as our understanding of them advances, predictive genetic testing may be used to determine which medicines to prescribe, and in what doses.
22 Some diseases, notably cancers, develop in cells which have an altered genetic constitution, so that the genetic make-up of the diseased tissue is no longer the same as that of the person in which it is present. Specific genes present in the diseased tissue may play a critical role in determining the optimum treatment. To establish this it will therefore be necessary to identify the genetic make-up of the cancer itself: testing the patient before a cancer has developed is of no use, because the genetic changes are only present in the cancer cells and not in the normal host tissues (see Box 2.3, Case study 2).
23 As more is learned about the vast subject of genetic variation which predisposes to disease, it is likely that newer, more precise classifications of common diseases will emerge (what has been called a molecular taxonomy of disease). Although this is still at a very early stage, it is likely that some conditions which are now considered to be single disorders, with a common set of symptoms, will be discovered to be more heterogeneous, with several different biochemical disorders leading to a common set of clinical features. In some of these cases, it may turn out that the nature and efficacy of treatment depends on which type of the disease is present. Such heterogeneity may be behind some of the well-known variation in efficacy of medicines given to people affected by what appears superficially to be the same disorder.
24 This stratification of groups of patients on the basis of genetic information has implications both for patients and for those involved in developing new medicines. There may be both positive and negative effects. Some potentially valuable new medicines may not be developed if, as a result of genetic stratification, the number of patients who would benefit is too small to be profitable. However, stratification may also enable some medicines to be developed that would otherwise have failed because the subgroup in which the medicine is effective can now be distinguished. It is currently uncertain which of these trends is likely to prevail. We therefore recommend that agencies responsible for the licensing of new medicines pay attention to the possible negative effects of stratification. If pharmacogenetic stratification does provide an economic disincentive for those developing new medicines, consideration should be given to preparing guidance notes that encourage applications to use existing orphan medicine legislation, or any other policy instrument with equivalent effect, to provide incentives for development. We further recommend that if orphan medicine legislation is to be applied, consideration is given by the International Conference on Harmonisation to a global approach to orphan medicine legislation. This should include reconsideration of the definition of an orphan medicine, with particular reference to the implications of genetic stratification of both patients and diseases (paragraph 4.40).