Designing pharmacogenetic projects in industry: practical design perspectives from the Industry Pharmacogenomics Working Group

Abstract

Pharmacogenetic association studies have the potential to identify variations in DNA sequence which impact drug response. Identifying these DNA variants can help to explain interindividual variability in drug response; this is the first step in personalizing dosing and treatment regimes to a patient's needs. There are many intricacies in the design and analysis of pharmacogenetic association studies, including having adequate power, selecting proper endpoints, detecting and correcting the effects of population stratification, modeling genetic and nongenetic covariates accurately, and validating the results. At this point there are no formal guidelines on the design and analysis of pharmacogenetic studies. The Industry Pharmacogenomics Working Group has initiated discussions regarding potential guidelines for pharmacogenetic study design and analyses (http://i-pwg.org) and the results from these discussions are presented in this paper.

Fulfilling the Promise of Personalized Medicine? Systematic Review and Field Synopsis of Pharmacogenetic Studies

“…These evaluations will require use of different metrics to those conventionally reported in discovery-based genetic studies (such as odds ratios or proportion of variance explained) [45], [46], [47]. Instead, sensitivity and specificity, predictive values and the generation of multivariate models that include genotype will need evaluating [42], [48]. In some cases, the most robust evaluation of the effectiveness of genetic tests may need to come from randomised trials comparing health outcomes among people randomised to pharmacogenetic testing or no testing, together with cost-effectiveness analyses as are now common when evaluating the usefulness of interventions.…”

Promises and challenges of pharmacogenetics: an overview of study design, methodological and statistical issues

“…43 However, since many pharmacogenetic studies use data from prospective studies, the study endpoints and patient population may not be precise enough to identify functional genes that are associated with the drug response. For example, it may be more appropriate to measure clinical outcomes, such as adverse bleeding events, when studying the association between safety measures and genetic markers.…”

Challenges Faced in the Integration of Pharmacogenetics/Genomics into Drug Development

“…The study designs used encompass cross-sectional studies, case-control studies and studies in cohorts in their natural settings in the absence of controls [35][36][37][38]. Lack of replication in these types of designs remains an important issue, often related to lack of robustness, of proper clinical end points, of careful phenotypic quality controls, and of appropriate statistical considerations [18]. These exploratory studies, mostly carried out postmarketing, are usually based on poorly selected cohorts limited in size, with lack of possibility to establish the predictive value, the sensitivity and the specificity for a pharmacogenetic marker.…”

“…Academic and professional societies have been central to the development of pharmacogenomic research, focusing mostly on well established drugs and usually publicly founded (Table 1). In parallel, the Industry Pharmacogenomics Working Group (http://i-pwg.org) has published practical perspectives regarding potential guidelines for pharmacogenomic study design and analyses [18].…”