Personalized Medicine : Pharmacogenetic Testing in Drug Development and Clinical Practice

Abstract

For drugs that are registered on the market, efficacy was proven on a population level. However, on an individual level, most drugs have a different effect in different patients. They may fail to work in some patients or cause serious side effects. Pharmacogenetic research studies the contribution of genetic variation to interindividual variability in response to medication. The aim is to optimize drug response for an individual patient by using his genetic profile in treatment decisions. In this thesis we investigated the use of pharmacogenetics throughout different phases of drug research as well as in day-to-day use in the post-marketing phase. Firstly, we studied which randomized controlled trial (RCT) designs are suitable for research aimed either to establish whether a subgroup of patients identified by genetic characteristics responds differently to the treatment, or to verify whether a proposed genotype-guided treatment is beneficial over standard care. In late phase drug development, involvement of pharmacogenetics may also influence the RCT design. The aim at that moment is to establish the benefit of the developed drug over placebo or an alternative treatment for the study population, though if there is evidence of effect modification by a genomic marker, the choice of study population and treatment may be complicated. We showed the potential benefit of adaptive RCT designs for such situations, which enable researchers to learn about the effect of the genetic variability on drug response and to immediately use this information for the remainder of the study. Secondly, we evaluated the value of pharmacogenetic testing in clinical practice in two different medical fields. We showed that genetic markers have added value over non-genetic factors in predicting whether a patient with elevated cholesterol levels will benefit from using a statin. Not only single polymorphisms but also gene-gene interactions seem valuable to examine in future modelling of statin response. In psychiatric practice, we showed that the presence of aberrant drug metabolism predicted by CYP2D6 and CYP2C19 impacts the consumption of care for patients using antidepressants and antipsychotics. Our results indicate that at this moment, knowledge of a patient’s predicted phenotype is not sufficient to avoid unsatisfactory drug responses and that genotype-guided treatment advices need to be improved. An important precondition for this type of research is the establishment of biobanks. We argue that an enhanced opt-in procedure is ethically necessary for the storage of samples from psychiatric patients. At this moment, only a small number of pharmacogenetic tests are currently routinely used in clinical practice. We conclude therefore with a discussion on potential barriers hindering the implementation of pharmacogenetic testing. We describe scientific, methodological and industrial barriers and focus on the apparent asymmetry between pharmacogenetic research aimed at drug safety and at drug efficacy.