REVIEW Pharmacogenomics in early-phase clinical development Pharmacogenomics (PGx) offers the promise of utilizing genetic fingerprints to predict individual responses to drugs in terms of safety, efficacy and pharmacokinetics. Early-phase clinical trial PGx applications can identify human genome variations that are meaningful to study design, selection of participants, allocation of resources and clinical research ethics. Results can inform later-phase study design and pipeline developmental decisions. Nevertheless, our review of the clinicaltrials.gov database demonstrates that PGx is rarely used by drug developers. Of the total 323 trials that included PGx as an outcome, 80% have been conducted by academic institutions after initial regulatory approval. Barriers for the application of PGx are discussed. We propose a framework for the role of PGx in early-phase drug development and recommend PGx be universally considered in study design, result interpretation and hypothesis generation for later-phase studies, but PGx results from underpowered studies should not be used by themselves to terminate drug-development programs. 1 KEYWORDS: clinical research n drug development n early-phase n PD n PGt n PGx Tal Burt* n pharmacodynamics n pharmacogenetics n pharmacogenomics n pharmacokinetics & Savita Dhillon2 n PK n POC n proof-of-concept 1Scientific Director, Duke Global Proof- of-Concept (POC) Research Network, Duke Clinical Research Unit (DCRU) & A genomic biomarker is defined as ‘a measur- decisions – an alternative to the ‘trial and error’ Duke Clinical Research Institute (DCRI); able DNA and/or RNA characteristic that is an approach. Both the US FDA and NIH have iden- Assistant Professor, Department of Psychiatry and Behavioral Sciences, indicator of normal biologic processes, patho- tified PGx as a key tool in the drug-development Duke University, Box 3854, Durham, genic processes and/or response to therapeutic or armamentarium [11,12] . This review will start NC 27710, USA other interventions’. Pharmacogenomics (PGx) with a general background of PGx, proceed with 2Medical Director, Medanta Duke Research Institute (MDRI), Medanta, is defined as ‘the study of variations of DNA and a discussion of PGx applications in early-phase The Medicity, Sector – 38, Gurgaon, RNA characteristics as related to drug response’. research and conclude with recommendations for Haryana 122 001, India *Author for correspondence: Pharmacogenetics is a subset of PGx and is defined future development of the field. PGx stakeholders [email protected] as ‘the study of variations in DNA sequence as to whom this review is addressed include drug related to drug response’ [1] . Another way of developers, clinical and preclinical investigators, thinking about the difference between pharma- biostatisticians, translational science experts and cogenetics and PGx is that the former deals with drug-development consultants, clinical research single genes and the latter with the entire human operators (early phase), analytics operators and genome [2,3]. PGx focuses on the predictive out- experts, business developers, healthcare payers, come of drug interventions as opposed to genomic regulators and policy makers. predictors of the natural course of illness, diag- nostics and prognostics (‘genomics’). PGx is the History study of the interaction between the drug and the PGx considerations, even before the term was in individual in terms of drug efficacy, safety and use, can be traced to ancient times [13] . The prin- pharmacokinetics (PK). It incorporates informa- ciple of personalized treatment tailored to some- tion from across the translational spectrum, from one’s physical and physiological constitution is gene–disease relationships through confirmatory long-held [14,15] . Pythagoras’ reluctance to pass clinical studies, into the development and even- through fava bean fields, possibly contributing tual application of new drugs [4]. PGx offers the to his death by captors, may have been due to his promise of delivering personalized and targeted recognition of his own glucose-6-phosphate dehy- drug therapy to those most likely to benefit from drogenase (G6PD) deficiency and the hemolytic it [5–8]. PGx may also contribute to the design anemia associated with consumption of fava beans and interpretation of clinical trials and improve [16,17]. Treating someone based on their body type effectiveness, safety and overall benefit:risk ratio or other constitutional factors, as is the practice in of drugs in development [9,10]. It has the poten- ancient Ayurveda, Chinese, Tibetan and Iranian tial for earlier arrival at informed developmental traditional medicine systems, incorporates genetic part of 10.2217/PGS.13.81 © Tal Burt Pharmacogenomics (2013) 14(9), 1085–1097 ISSN 1462-2416 1085 REVIEW Burt & Dhillon Pharmacogenomics in early-phase clinical development REVIEW features into treatment considerations [13–15,18,19]. or hypothesized to impact specific pathways Evidence-based medicine may have yet to vali- relevant to drug response (e.g., CYP2D6 date some claims of traditional medicine, but metabolism) [34]. These studies are hypothesis- these examples demonstrate that the principles driven with predetermined and limited num- of PGx and related personalized medicine were bers of specific genetic associations between the long part of medical approaches and practice. pharmacological intervention and its outcomes. More recently, at the dawn of a modern trend, The disadvantage of the approach is that it may the advent of PGx as a science and development overlook associations with unknown and unan- tool was first conceptualized by Motulsky in 1957 ticipated genetic candidates. The advantage is [20–22]. A twin study of dicumarol pharmaco- the small number of analyses and the often kinetics provided the first evidence of genetic- large effect sizes [34,35]. This has been the first based pharmaco kinetics [23]. Another example of approach to be used in PGx studies because it a PGx-guided individualized intervention that did not require access to the full human may not be thought of as such but has been prac- genome, available only since 2000 [23,34]. ticed for decades is anesthesia, where the doses of Genome-wide association studies (GWAS) the anesthetics are continuously adapted to the involve comparing two groups of individuals individual’s signs and symptoms [24]. with differing characteristics (e.g., drug response) and identifying associations with Background many known genetic variants. Since the genetic There are many interindividual differences in variants are chosen without prior knowledge or response to drug therapy, many may not matter, suspicion of an association with the differing but some do and may pertain to the interaction of clinically relevant phenotypes (e.g., disease, drug with genetically determined physiological responses to treatment), GWAS studies are con- and pathophysiological mechanisms. The differ- sidered an unbiased, ‘agnostic’ approach [36]. ences that matter pertain to three main catego- GWAS may assess associations of up to 1 mil- ries or domains of study in PGx: PK, beneficial lion genetic variants with clinically relevant pharmacodynamics (PD; beneficial, or efficacy), outcomes [37]. Associations found in GWAS do and adverse PD (adverse or toxicity). In every not necessarily imply causality of the identified step of PK, or the processes that govern what the genetic marker in the variation of the pheno- body does to the drug (principally absorption, type. Hence, follow-up studies on the impact distribution, metabolism and excretion), there of modifications in gene expression on the phe- could be genetic variability in the following: notype are required [4]. The multiple associa- gastro intestinal tract environment and absorp- tions studied require adequate statistical correc- tion, active transport across membranes, metab- tions. With a few notable exceptions and not- olism, protein binding. Similarly, genetic traits withstanding the relatively small numbers can impact a drug’s PD, or the mechanism(s) tested so far using GWAS, it appears that PGx governing the drug’s actions at its targets (drug- effect sizes using GWAS are usually small [34,35]. related phenotypes [4]). The impact of inter- species genomic differences (between rhesus Whole-exome and whole-genome sequencing monkeys and humans) on a drug’s target bind- – the most comprehensive approach that ana- ing and consequent dramatic clinical manifesta- lyzes the entire human genetic material for tions is exemplified by the first-in-man study of variants relevant to drug response [35]. It may the anti-CD28 monoclonal antibody TGN1412 help identify novel or very rare variants that [25,26]. Genetic differences in response to drugs would not be discovered via GWAS, but nev- (e.g., due to CYP450 polymorphisms and G6PD ertheless may need to be combined with deficiency) may be inter- or intra-ethnic [17,27–30] . GWAS to evaluate associations with drug PGx principles may inform drug developers’ response. Although interpreting such data marketing strategies and healthcare providers’ would be difficult. With reduced cost of insurance policies [31–33]. whole-genome sequencing (at ~US$3000 in Three main PGx approaches are applied in 2012 [4]) this approach is expected to become drug development: the dominant PGx approach. Candidate gene studies. Also called mono- genetic (or simply genetic rather than the below Uses in clinical practice genomic approaches) or targeted pathway ana- Personalized