Pharm-econogenomics: a new appraisal.

Pharmacogenomics is poised to radically alter the way drugs are designed, developed, and prescribed. Given that much of the variation in drug response can be attributed to genetic differences, tailoring drugs to an individual’s unique genetic signature provides the opportunity to reduce adverse drug events, improve drug efficacy, optimize trial design, and prevent costly drug recalls (1 ). Developing pharmacogenomic strategies to address these issues is critical, given that lack of efficacy and adverse drug events cost the US well over $100 billion annually and that the overall cost for developing a single drug now exceeds $1 billion (2– 4 ). Although genomewide association studies have identified, in general, common sequence variants with increased risks in susceptibility of only 10%–20%, the odds ratios for major side effects or drug responsiveness have been exceptionally large, such as 3to 20-fold (an increase in risk of 300% to 2000%). This large difference is likely attributable to the fact that humans have been exposed, in evolutionary terms, to most drugs only for a relatively short period of time and that limited genetic selection pressures have been applied (4 ). Accordingly, exploiting the marked interaction of the genome with drug response represents an exceptional opportunity to enhance the precision and lower the costs of prescription medications. This opportunity has been enhanced by the plummeting cost of sequencing and the recent precedents of accelerated regulatory drug approvals for breakthrough medications developed with genomic guidance (5 ). Although pharmacogenomics offers the prospect of distinct improvements in drug development and utilization, it is appropriate to ask whether this approach will be cost-effective. In this issue of Clinical Chemistry, Arnaout et al. describe a cost-effectiveness analysis of the costs and time scales involved in the discovery of pharmacogenomic variants, their validation, and their incorporation into future clinical guidelines (3 ). A selection of 8 currently approved drugs—including warfarin, clopidogrel, statins, and carbamazepine—that already have evidence for pharmacogenomic guidance was the basis of a quantitative model designed to simulate future time scales and development costs for a set of hypothetical drugs. Cost calculations were based on factors that included cost per genomic association, number of associations per adverse outcome, and estimates of costs to produce a clinical guideline based on the previously selected prescription drugs. Calculations of time-scale parameters were based on the time from variant discovery to inclusion in a set of validated clinical guidelines. Given estimates that up to 83% of adverse drug events are nonpreventable and therefore potentially genetic in origin, a value of 60% was chosen as an estimate of the potential reduction in the incidence of adverse drug events. Simulations were run for each hypothetical drug to estimate the time and costs to discover, validate, and produce a validated guideline for reducing an adverse event. This process was repeated until adverse events for that particular drug were reduced by at least 50%. It is interesting that the single greatest determinant of total cost was the extent to which genomic variants influenced the likelihood of an adverse drug event—a component that is likely only to improve over time. The authors estimate that an overall reduction in adverse events by 25% to 50%, would require an investment in the single-digit billions of dollars for a period of up to 20 years (3 ). Arnaout et al. have addressed hypothetically the issue of costs associated with pharmacogenomic drug development. As they acknowledge, there is considerable variation and uncertainty associated with their model. We believe that the projected worst-case scenario of a cost of up to $6 billion over 20 years is justifiable, given the pharmaceutical costs of misdirected therapies of $100 billion in the US alone, whether for engendering noxious side effects or for lack of efficacy in patients (4 ). Pharmacogenomics is ideally positioned to address such wasted costs and potentially avoidable adverse effects of drugs. Our belief is that all future drug development will be genomically or biomarker (including biosensor) guided and that its largescale adoption will lead to more efficacious and safer drugs that are delivered at considerably lower costs. The question of pharmacogenomic cost-effectiveness has previously been addressed with respect to other prescription medications, such as warfarin, but such studies suffer, as do the calculations by Arnaout et al., 1 Scripps Translational Science Institute, La Jolla, CA; 2 Scripps Health, La Jolla, CA. * Address correspondence to this author at: Scripps Translational Science Institute, 3344 N. Torrey Pines Court, Suite 300, La Jolla, CA 92037. Fax 858-5469272; e-mail [email protected]. Received January 21, 2013; accepted January 24, 2013. Previously published online at DOI: 10.1373/clinchem.2012.200386 Clinical Chemistry 59:4 592–594 (2013) Editorials