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Preemptive pharmacogenetic testing aims to optimize medication use by having genetic information at the point of prescribing. Payers' decisions influence implementation of this technology. We investigated US payers' knowledge, awareness, and perspectives on preemptive pharmacogenetic testing. A qualitative study was conducted using semistructured interviews. Participants were screened for eligibility through an online survey. A blended inductive and deductive approach was used to analyze the transcripts. Two authors conducted an iterative reading process to code and categorize the data. Medical or pharmacy directors from 14 payer organizations covering 122 million US lives were interviewed. Three concept domains and ten dimensions were developed. Key findings include clinical utility concerns and limited exposure to preemptive germ-line testing, continued preference for outcomes from randomized controlled trials, interest in guideline development, importance of demonstrating an impact on clinical decision making, concerns of downstream costs and benefit predictability, and the impact of public stakeholders such as the Food and Drug Administration and Centers for Medicare and Medicaid Services. Both barriers and potential facilitators exist to developing cohesive reimbursement policy for pharmacogenetics, and there are unique challenges for the preemptive testing model. Prospective outcome studies, more precisely defining target populations, and predictive economic models are important considerations for future research.

Interindividual variability in drug efficacy and toxicity is a major challenge in clinical practice. Variations in drug pharmacokinetics (PKs) and pharmacodynamics (PDs) can be, in part, explained by polymorphic variants in genes encoding drug metabolizing enzymes and transporters (absorption, distribution, metabolism, and excretion) or in genes encoding drug receptors. Pharmacogenomics (PGx) has allowed the identification of predictive biomarkers of drug PKs and PDs and the current knowledge of genome‐disease and genome‐drug interactions offers the opportunity to optimize tailored drug therapy. High‐throughput PGx genotyping, from targeted to more comprehensive strategies, allows the identification of PK/PD genotypes to be developed as clinical predictive biomarkers. However, a biomarker needs a robust process of validation followed by clinical‐grade assay development and must comply to stringent regulatory guidelines. We here discuss the methodological challenges and the emerging technological tools in PGx biomarker discovery and validation, at the crossroad among molecular genetics, bioinformatics, and clinical medicine.

Prediction of phenotypic consequences of mutations constitutes an important aspect of precision medicine. Current computational tools mostly rely on evolutionary conservation and have been calibrated on variants associated with disease, which poses conceptual problems for assessment of variants in poorly conserved pharmacogenes. Here, we evaluated the performance of 18 current functionality prediction methods leveraging experimental high-quality activity data from 337 variants in genes involved in drug metabolism and transport and found that these models only achieved probabilities of 0.1–50.6% to make informed conclusions. We therefore developed a functionality prediction framework optimized for pharmacogenetic assessments that significantly outperformed current algorithms. Our model achieved 93% for both sensitivity and specificity for both loss-of-function and functionally neutral variants, and we confirmed its superior performance using cross validation analyses. This novel model holds promise to improve the translation of personal genetic information into biological conclusions and pharmacogenetic recommendations, thereby facilitating the implementation of Next-Generation Sequencing data into clinical diagnostics.

Successfully implementing pharmacogenomics into routine clinical practice requires an efficient process to order genetic tests and report the results to clinicians and patients. Lack of standardized approaches and terminology in clinical laboratory processes, ordering of the test and reporting of test results all impede this workflow. Expert groups such as the Association for Molecular Pathology and the Clinical Pharmacogenetics Implementation Consortium have published recommendations for standardizing laboratory genetic testing, reporting and terminology. Other resources such as PharmGKB, ClinVar, ClinGen and PharmVar have established databases of nomenclature for pharmacogenetic alleles and variants. Opportunities remain to develop new standards and further disseminate existing standards which will accelerate the implementation of pharmacogenomics.

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.

CYP2D6 is one of the most studied enzymes in the field of pharmacogenetics. The CYP2D6 gene is highly polymorphic with over 100 catalogued star (*) alleles, and clinical CYP2D6 testing is increasingly accessible and supported by practice guidelines. However, the degree of variation at the CYP2D6 locus and homology with its pseudogenes make interrogating CYP2D6 by short-read sequencing challenging. Moreover, accurate prediction of CYP2D6 metabolizer status necessitates analysis of duplicated alleles when an increased copy number is detected. These challenges have recently been overcome by long-read CYP2D6 sequencing; however, such platforms are not widely available. This review highlights the genomic complexities of CYP2D6, current sequencing methods and the evolution of CYP2D6 from allele discovery to clinical pharmacogenetic testing.

Pharmacogenomic (PGx) testing using multi‐gene panels (mgPGx) is documented to improve clinical outcomes; however, real‐world data on its economic impact remain limited. This study aimed to evaluate the utility and economic value of mgPGx testing among Medicare patients within a community‐based health system. We identified Medicare Advantage patients within the primary care setting of a community‐based health system hospital who were taking ≥ 1 PGx‐guided medication using a stratification algorithm. In total, 1042 patients participated in mgPGx testing. We evaluated the prevalence of PGx medications, polypharmacy involving PGx medications, and actionable results (i.e., a phenotype with PGx guidance and a relevant PGx medication). A Total Cost of Care (TCOC) analysis was performed for a subset of patients (n = 548) who underwent PGx testing and were matched to a control group that did not undergo PGx testing using propensity score matching. Total medical expenses over 12 months, both before and after testing, were compared. Forty‐four percent (n = 454/1042) of patients were ≥ 3 PGx‐guided medications. Over one‐third of patients who were on ≥ 3 PGx medications had ≥ 2 actionable results (35.5%, n = 161/454). The TCOC analysis demonstrated a trend toward a net cost savings of$1827 per member per year (PMPY), with $ 1582 in medical savings and $245 in pharmacy savings. Polypharmacy with PGx medications is prevalent, and mgPGx led to cost savings. Further research with a larger sample size is needed to replicate the results and assess the long‐term impact on healthcare utilization and costs.

Pharmacogenomics (PGx) is a rapidly evolving field that aims to personalize medicine by identifying genetic variations that influence drug response. While next-generation sequencing (NGS)-based applications are not yet widely adopted in clinical routine, this study aimed to validate 9 genes of the NGS-based Ion AmpliSeq Pharmacogenomics Panel on 28 samples with known diplotypes for routine clinical implementation at Bumrungrad International Hospital (BIH). The panel was evaluated for accuracy (> 96.77%), sensitivity (100%), specificity (> 95.31%), positive predictive value (PPV; > 90.63%), negative predictive value (NPV; 100%), and reproducibility (> 99.85%). A novel bioinformatics pipeline, BIH-protocol, was specifically developed and designed to mitigate errors across all measurement metrics, ensuring reliability and accuracy of test results, even in individuals with complex genetic backgrounds. These results demonstrate 100% precision and reliability of the Ion AmpliSeq Pharmacogenomics Panel together with BIH-protocol for genetic variation detection. These findings demonstrate the panel's suitability for integration into routine clinical practice and its potential to advance personalized medicine.

Evaluate the cost–effectiveness of combinatorial pharmacogenomic (PGx) testing, versus treatment as usual (TAU), to guide treatment for patients with depression, from the Canadian public healthcare system perspective. Clinical and economic data associated with depression were extracted from published literature. Clinical (quality-adjusted life years; QALYs) and economic (incremental cost–effectiveness ratio) outcomes were modeled using combinatorial PGx and TAU treatment strategies across a 5-year time horizon. With the combinatorial PGx strategy to guide treatment, patients were projected to gain 0.14–0.19 QALYs versus TAU. Accounting for test price, combinatorial PGx saved CAD $1,687–$3,056 versus TAU. Incremental cost–effectiveness ratios ranged from -$11,861 to -$16,124/QALY gained. Combinatorial PGx testing was more efficacious and less costly compared with the TAU for depression.

Background Pharmacogenetics offers the potential to improve health outcomes by identifying individuals who are at greater risk of harm from certain medicines. Routine adoption of pharmacogenetic tests requires evidence of their cost effectiveness. Objective The present review aims to systematically review published economic evaluations of pharmacogenetic tests that aim to prevent or reduce the incidence of ADRs. Methods We conducted a systematic literature review of economic evaluations of pharmacogenetic tests aimed to reduce the incidence of adverse drug reactions. Literature was searched using Embase, MEDLINE and the NHS Economic Evaluation Database with search terms relating to pharmacogenetic testing, adverse drug reactions, economic evaluations and pharmaceuticals. Titles were screened independently by two reviewers. Articles deemed to meet the inclusion criteria were screened independently on abstract, and full texts reviewed. Results We identified 852 articles, of which 47 met the inclusion criteria. There was evidence supporting the cost effectiveness of testing for HLA - B*57:01 (prior to abacavir), HLA - B*15:02 and HLA - A*31:01 (prior to carbamazepine), HLA - B*58:01 (prior to allopurinol) and CYP2C19 (prior to clopidogrel treatment). Economic evidence was inconclusive with respect to TPMT (prior to 6-mercaptoputine, azathioprine and cisplatin therapy), CYP2C9 and VKORC1 (to inform genotype-guided dosing of coumarin derivatives), MTHFR (prior to methotrexate treatment) and factor V Leiden testing (prior to oral contraception). Testing for A1555G is not cost effective before prescribing aminoglycosides. Conclusions Our systematic review identified robust evidence of the cost effectiveness of genotyping prior to treatment with a number of common drugs. However, further analyses and (or) availability of robust clinical evidence is necessary to make recommendations for others.