Initiatives Seek to Demonstrate Clinical Utility of Premptive PGx Testing

The application of pharmacogenomics (PGx) into routine, clinical care remains very limited, despite its potential to improve drug and dose selection based upon one's genes. Two new reviews, one published online Dec. 27, 2016 in Clinical Pharmacology & Therapeutics (CP&T) and one published in the December issue of the European Journal of Human Genetics, highlight both the challenges impeding translation of PGx into the clinic, as well as the surging number of implementation initiatives ongoing in the United States and Europe. Experts are optimistic that the evidence generated from these implementation initiatives will not only drive clinical adoption of PGx, but will shift momentum towards implementation of preemptive PGx testing strategies.

"Since actionable PGx variants are ubiquitous and the results of PGx testing are life-long, we foresee a future where everyone undergoes PGx testing," writes lead author Cathelijne H. van der Wouden, from Leiden University Medical Centre (the Netherlands), in CP&T. "We consider that quantifying the collective clinical utility of a panel of PGx markers to be more relevant than providing evidence for individual drug-gene pairs. This will, however, still require the systematic implementation of a pre-emptive PGx."

Evidence shows the majority of people have at least one actionable PGx variant. PGx testing holds the promise to make prescribing safer, more effective, and, in theory, more cost-effective by eliminating trial and error prescribing patterns. Yet, barriers exist to implementing widespread PGx testing because of inadequate understanding about testing selection, limited guidelines directing clinical use, and inadequate integration of information technology with clinical workflow.

Commercial genotyping microarrays can inform PGx-related treatment decisions at a cost of less than $50. This price point, experts believe, is low enough to encourage wide-scale augmentation of electronic health records with PGx information, even before the need for medication arises. However, the authors caution that the evidence base remains limited for demonstrating the clinical utility and the cost-effectiveness of pre-emptive testing.

Filling the Evidence Gaps
To date, PGx investigations have disproportionately focused on clinical discovery and validation instead of clinical translation, which must address barriers both at the clinic level (workflow and IT implementation challenges) and at the national level (reimbursement policies and development of guidelines). Now, though, there are an increasing number of large-scale initiatives implementing PGx in clinical settings, including how to integrate PGx test results into electronic health records and clinical decision support systems.

The newest initiative, the Ubiquitous Pharmacogenomics Consortium, which has been funded (€ 15 million) by the European Commission's Horizon-2020 program, aims to fill in evidence gaps related to patient outcomes and cost effectiveness of pre-emptive PGx in real-world settings. The consortium is conducting a prospective, block-randomized, controlled clinical study called PREPARE (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions), in which 8,000 patients throughout Europe (United Kingdom, the Netherlands, Austria, Greece, Slovenia, Italy and Spain) will undergo pre-emptive genotyping using a polymerase chain reaction-based panel of 50 variants in 13 pharmacogenes to guide drug and dose selection for 43 drugs. Prior to the launch of the trial, organizers developed clinical decision support systems, clinical guidelines, and provider training and education

As of Dec. 8, 2016 there are 233 drugs labels on the FDA's Table of Pharmacogenomic Biomarkers in Drug Labels.

	Genetic Testing Required	Genetic Testing Recommended	Actionable PGx*
FDA	46	5	143
EMA	31	-	14

* Drug label does not mention gene, protein, or chromosomal testing, but it contains information about changes in efficacy, dosage or toxicity due to such variants

Source: Adapted from "Drug Labels" by PharmGKB.

regarding PGx. The consortium believes that implementing PGx-guided drug and dose selection will decrease clinically relevant adverse drug reactions by 30 percent.

In the United States, there are more than eight ongoing implementation efforts. Some, including Right Drug, Right Dose, Right Time (RIGHT) at the Mayo Clinic, the 1,200 Patients Project at University of Chicago, PG4KDS at St. Jude Children's Research Hospital, INdiana GENomics Implementation: an Opportunity for the Under Served (INGENIOUS) at Indiana University, and the multi-center Pharmacogenomics Research Network (PGRN) Translational Pharmacogenetics Program are all putting pre-emptive PGx testing into clinical practice.

Takeaway: While PGx has seen slow uptake in routine, clinical practice, experts believe evidence emerging from new large-scale implementation initiatives will demonstrate the clinical utility and cost-effectiveness of pre-emptive PGx testing strategies.