Pharmacogenomic knowledge and awareness among diverse patients treated with angiotensin converting enzyme inhibitors.

We developed novel electronic phenotyping algorithms for the BioMe biobank data, which accurately identified angiotensin converting enzyme inhibitor (ACEi)-induced angioedema cases and controls. A survey was mailed to all 1075 patients and 91 were returned. Over a third reported that prescribing physicians had not discussed with them the concepts of interindividual drug response variability or adverse event risk, and 73% of patients were previously unaware of pharmacogenomics; however, most patients were interested in having pharmacogenomic testing. Moreover, 67% of patients indicated that pharmacogenomic testing would positively influence their medication compliance. In addition to identifying an innovative approach to define biobank cohorts for pharmacogenomic studies, these results indicate that patients are interested in pharmacogenomic testing, which could translate to improved adherence.

Prescriber Adoption of SLCO1B1 Genotype-Guided Simvastatin Clinical Decision Support in a Clinical Pharmacogenetics Program.

Pharmacogenetic implementation programs are increasingly feasible due to the availability of clinical guidelines for implementation research. The utilization of these resources has been reported with selected drug-gene pairs; however, little is known about how prescribers respond to pharmacogenetic recommendations for statin therapy. We prospectively assessed prescriber interaction with point-of-care clinical decision support (CDS) to guide simvastatin therapy for a diverse cohort of primary care patients enrolled in a clinical pharmacogenetics program. Of the 1,639 preemptively genotyped patients, 298 (18.2%) had an intermediate function (IF) OATP1B1 phenotype and 25 (1.53%) had a poor function (PF) phenotype, predicted by a common single nucleotide variant in the SLCO1B1 gene (c.521T>C; rs4149056). Clinicians were presented with CDS when simvastatin was prescribed for patients with IF or PF through the electronic health record. Importantly, 64.2% of the CDS deployed at the point-of-care was accepted by the prescribers and resulted in prescription changes. Statin intensity was found to significantly influence prescriber adoption of the pharmacogenetic-guided CDS, whereas patient gender or race, prescriber type, or pharmacogenetic training status did not significantly influence adoption. This study demonstrates that primary care providers readily adopt pharmacogenetic information to guide statin therapy for the majority of patients with preemptive genotype data.

Implementing a pragmatic clinical trial to tailor opioids for acute pain on behalf of the IGNITE ADOPT PGx investigators.

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing.

PURPOSE: The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear. METHODS: In this report, we compare and contrast implementation strategies for pre-emptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates. RESULTS: We found that while pre-emptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Finally, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for pre-emptive PGx testing remain low. CONCLUSION: These findings should inform the establishment of future implementation efforts at institutions considering a pre-emptive PGx testing program.

Pharmacy students' attitudes and perceptions toward pharmacogenomics education.

PURPOSE: To evaluate final-year pharmacy students' perceptions toward pharmacogenomics education, their attitudes on its clinical relevance, and their readiness to use such knowledge in practice. METHODS: A 19-question survey was developed and modified from prior studies and was pretested on a small group of pharmacogenomics faculty and pharmacy students. The final survey was administered to 978 final-year pharmacy students in 8 school/colleges of pharmacy in New York and New Jersey between January and May 2017. The survey targeted 3 main themes: perceptions toward pharmacogenomics education, attitudes toward the clinical relevance of this education, and the students' readiness to use knowledge of pharmacogenomics in practice. RESULTS: With a 35% response rate, the majority (81%) of the 339 student participants believed that pharmacogenomics was a useful clinical tool for pharmacists, yet only 40% felt that it had been a relevant part of their training. Almost half (46%) received only 1-3 lectures on pharmacogenomics and the majority were not ready to use it in practice. Survey results pointed toward practice-based trainings such as pharmacogenomics rotations as the most helpful in preparing students for practice. CONCLUSIONS: Final-year student pharmacists reported varying exposure to pharmacogenomics content in their pharmacy training and had positive attitudes toward the clinical relevance of the discipline, yet they expressed low confidence in their readiness to use this information in practice.

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing.

PURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.

Views Of Primary Care Providers On Testing Patients For Genetic Risks For Common Chronic Diseases.

We surveyed 488 primary care providers in community and academic practices in New York City in the period 2014-16 about their views on genetic testing for chronic diseases. The majority of the providers, most of whom were current or recent physicians in training, had had formal genetics education and had positive views of the utility of genetic testing. However, they felt unprepared to work with patients at high risk for genetic conditions and were not confident about interpreting test results. Many were concerned that genetic testing might lead to insurance discrimination and lacked trust in companies that offer genetic tests. These findings point to some of the attitudes and knowledge gaps among the providers that should be considered in the clinical implementation of genomic medicine for chronic conditions. Enhanced training, guidelines, clinical tools, and awareness of patient protections might support the effective adoption of genomic medicine by primary care providers.

Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study.

There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments-approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3%) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.

Genetic Determinants of P2Y12 Inhibitors and Clinical Implications.

There is significant interpatient variability in clopidogrel effectiveness, which is due in part to cytochrome P450 (CYP) 2C19 genotype. Approximately 30% of individuals carry CYP2C19 loss-of-function alleles, which have been consistently shown to reduce clopidogrel effectiveness after an acute coronary syndrome and percutaneous coronary intervention. Guidelines recommend consideration of prasugrel or ticagrelor in these patients. A clinical trial examining outcomes with CYP2C19 genotype-guided antiplatelet therapy is ongoing. In the meantime, based on the evidence available to date, several institutions have started clinically implementing CYP2C19 genotyping to assist with antiplatelet selection after percutaneous coronary intervention.

Clinical pharmacogenetics implementation: approaches, successes, and challenges.

Current challenges exist to widespread clinical implementation of genomic medicine and pharmacogenetics. The University of Florida (UF) Health Personalized Medicine Program (PMP) is a pharmacist-led, multidisciplinary initiative created in 2011 within the UF Clinical Translational Science Institute. Initial efforts focused on pharmacogenetics, with long-term goals to include expansion to disease-risk prediction and disease stratification. Herein we describe the processes for development of the program, the challenges that were encountered and the clinical acceptance by clinicians of the genomic medicine implementation. The initial clinical implementation of the UF PMP began in June 2012 and targeted clopidogrel use and the CYP2C19 genotype in patients undergoing left heart catheterization and percutaneous-coronary intervention (PCI). After 1 year, 1,097 patients undergoing left heart catheterization were genotyped preemptively, and 291 of those underwent subsequent PCI. Genotype results were reported to the medical record for 100% of genotyped patients. Eighty patients who underwent PCI had an actionable genotype, with drug therapy changes implemented in 56 individuals. Average turnaround time from blood draw to genotype result entry in the medical record was 3.5 business days. Seven different third party payors, including Medicare, reimbursed for the test during the first month of billing, with an 85% reimbursement rate for outpatient claims that were submitted in the first month. These data highlight multiple levels of success in clinical implementation of genomic medicine.

Physician Attitudes toward Adopting Genome-Guided Prescribing through Clinical Decision Support.

This study assessed physician attitudes toward adopting genome-guided prescribing through clinical decision support (CDS), prior to enlisting in the Clinical Implementation of Personalized Medicine through Electronic Health Records and Genomics pilot pharmacogenomics project (CLIPMERGE PGx). We developed a survey instrument that includes the Evidence Based Practice Attitude Scale, adapted to measure attitudes toward adopting genome-informed interventions (EBPAS-GII). The survey also includes items to measure physicians' characteristics (awareness, experience, and perceived usefulness), attitudes about personal genome testing (PGT) services, and comfort using technology. We surveyed 101 General Internal Medicine physicians from the Icahn School of Medicine at Mount Sinai (ISMMS). The majority were residency program trainees (~88%). Prior to enlisting into CLIPMERGE PGx, most physicians were aware of and had used decision support aids. Few physicians, however, were aware of and had used genome-guided prescribing. The majority of physicians viewed decision support aids and genotype data as being useful for making prescribing decisions. Most physicians had not heard of, but were willing to use, PGT services and felt comfortable interpreting PGT results. Most physicians were comfortable with technology. Physicians who perceived genotype data to be useful in making prescribing decisions, had more positive attitudes toward adopting genome-guided prescribing through CDS. Our findings suggest that internal medicine physicians have a deficit in their familiarity and comfort interpreting and using genomic information. This has reinforced the importance of gathering feedback and guidance from our enrolled physicians when designing genome-guided CDS and the importance of prioritizing genomic medicine education at our institutions.