PGx Adoption Still Slow; Outcomes Benefits Inconclusive

One of the linchpins of personalized medicine is the utilization of pharmacogenomic testing to individualize treatment options. Yet adoption of pharmacogenomic testing has not materialized as hoped, in part because of a lack of data showing the clear outcomes benefits resulting from testing. Several recently published studies highlight the continued interest in pharmacogenomic testing and the barriers to adoption. “Pharmacogenomics is one of my interests and one of my struggles. I am an optimist, but the definition of a pessimist is a very well informed optimist and with pharmacogenomics we are very well informed,” joked Domnita Crisan, M.D., Ph.D., Beaumont Health System (Royal Oak, Mich.) during her presentation at G2 Intelligence’s 31st annual Lab Institute (Arlington, Va.; Oct. 16-18). “We are still in the hope stage.” Crisan cites data showing that 24 percent of U.S. outpatients could potentially benefit from using pharmacogenomic information to guide therapy choice and dosing. Yet data, including from her own experience, show adoption is substantially below that. In 2012 pharmacogenomic tests accounted for 0.36 percent of total testing at Beaumont. Crisan says at her institution pharmacogenomic testing is ordered more often in patients compliant with their medication, for whom symptoms persist, rather than at treatment initiation. Pharmacogenomics in Psychiatry In psychiatry, a medical specialty where treatment nonresponsiveness is a widespread problem and drugs’ side effects can be so severe patients discontinue treatment, testing of pharmacogenomic variants CYP2D6 and CYP2C19 may hold meaningful clinical potential. A recent review published in the October issue of the International Review of Psychiatryfound that testing may be beneficial in improving psychotropic drug outcomes, particularly for nonextensive metabolizing patients. The notorious variability in psychiatric drug treatment response is believed to be influenced, at least in part, by variation in genes. CYP2D6 is involved in the metabolism of 80 percent of anti-psychotics and anti-depressants. The review examined published studies from 2008 to 2013. Studies, which were limited by small sample sizes, showed mixed results regarding the impact of CYP2D6 and CYP2C19 gene variation on treatment response. Associations were seen most often between drug plasma levels and CYP metabolizer status. Also, nonextensive CYP2D6 or CYP2C19 metabolizers seemed to have higher occurrence and severity of side effects. “More research is needed to further elucidate the benefits from CYP2D6 and CYP2C19 genetic testing in clinical practice and to determine for which drugs testing may be particularly important,” conclude the authors, led by Daniel J. Müller, from University of Toronto in Canada. “Given that other genes will ultimately also modulate response and side effects to psychotropic medication, the ‘ideal’ genetic test will be based on an algorithm including several genes and multiple gene variants, and once validated, such test will significantly improve psychiatric drug treatment.” Payers are also interested in comprehensive cost-benefit analyses for pharmacogenomic testing, demonstrating that the cost of the testing itself is justified by downstream cost savings. Better establishment of reimbursement and inclusion of pharmacogenomics in guidelines will likely aid adoption efforts. Pharmacogenomic testing is slowly beginning to permeate psychotropic drug labels and guidelines. For instance, the Clinical Pharmacogenetics Implementation Consortium proposed tricyclic anti-depressants dosage recommendations that incorporated different combinations of CYP2D6 and CYP2C19 metabolizer status. Additionally, the U.S. Food and Drug Administration recently issued a black box warning to not exceed 4 mg per day of pimozide in children who are CYP2D6 poor metabolizers. Implementation in Clinical Practice Hope still exists, though, that additional data will drive adoption of more pharmacogenomic testing in routine clinical practice. According to a study published in the June 10 issue of the Journal of Personalized Medicine, 15 percent of the 10,000 physicians participating in a survey report ordering a pharmacogenomic test in past six months, while 31.5 percent anticipate ordering a test in next six months. At the University of Toronto’s Centre for Addiction and Mental Health, reporting of CYP2D6 and CYP2C19 genotype information has been routine, particularly in nonresponders, since 2009. Müller and colleagues surveyed physicians at his institution regarding preliminary impressions of utilization of pharmacogenomic results. They found that providing genotypic information is feasible and generally well accepted by both patients and physicians. There were more nonextensive metabolizers for both enzymes than expected, indicating that past poor drug outcome was probably associated to an “abnormal” metabolizer status, the authors say. Genomic results were generally “very well understood” by physicians. Several patients were “much improved” after genotypic information was considered and importantly, no cases of deterioration following the genetic testing were reported. Takeaway: Routine pharmacogenomic testing adoption has been slower than anticipated, but a generation of new data demonstrating improved clinical outcomes and downstream cost savings as a result of testing may drive future adoption. Side Bar Box: Large-Scale Study to Use Pharmacogenomics to Improve Cardiology Care For patients requiring anti-coagulation therapy for a cardiovascular indication, genotype-guided dosing of warfarin and comparable drugs might have some benefit, but the results are far from clear. Three separate trials published in the Nov. 19 issue of the New England Journal of Medicine to coincide with the American Heart Association Scientific Sessions 2013 (Dallas; Nov. 16-20), showed mixed results for the effectiveness of genotyping in dosing warfarin, compared to utilizing clinical factors alone. In order to develop more definitive data to resolve lingering confusion in the cardiology community, a large-scale effort is under way to focus on whether pharmacogenomics leads to better medication decisions that ultimately can improve patient outcomes and conserve financial resources, if more expensive anti-platelet medications aren’t necessary to achieve similar results. “The current standard of care after angioplasty is to prescribe clopidogrel for one year, regardless of a person’s individual genotype, even though we have known for several years that variation in the CYP2C19 gene may diminish the benefit from the drug,” says Naveen Pereira, M.D., principal investigator of the new effort at the Mayo Clinic, in a statement. “What we don’t know—and why there is such confusion in the cardiovascular community—is how these genetic changes affect long-term clinical outcomes and whether we can decrease overall health care costs.” The Mayo Clinic is leading the Tailored Antiplatelet Therapy to Lessen Outcomes after Percutaneous Coronary Intervention study to determine whether prescribing heart medication based on a patient’s CYP2C19 genotype will help prevent adverse cardiovascular outcomes in patients who undergo percutaneous coronary intervention, commonly called angioplasty. This large study (15 sites in the United States, Canada, and South Korea) will address the two most pressing concerns of bringing pharmacogenomics testing to the clinic—the outcomes benefits and cost-effectiveness of testing. “This study examines as much as an $8 billion question in health care,” says Nilay Shah, Ph.D., a Mayo Clinic professor who will work on the financial analysis. “Clopidogrel is the second-most prescribed medication in the United States, and although ticagrelor costs much more, the costs of taking patients into the emergency room and performing a second angioplasty are much higher.”