Implementation of a pharmacogenomic program in a Brazilian public institution.

This narrative review describes implementation, current status and perspectives of a pharmacogenomic (PGx) program at the Brazilian National Cancer Institute (INCA), targeting the cancer chemotherapeutic drugs - fluoropyrimidines, irinotecan and thiopurines. This initiative, designed as a research project, was supported by a grant from the Brazilian Ministry of Health. A dedicated task force developed standard operational procedures from recruitment of patients to creating PGx reports with dosing recommendations, which were successfully applied to test 100 gastrointestinal cancer INCA outpatients and 162 acute lymphoblastic leukemia pediatric patients from INCA and seven other hospitals. The program has been subsequently expanded to include gastrointestinal cancer patients from three additional cancer treatment centers. We anticipate implementation of routine pre-emptive PGx testing at INCA but acknowledge challenges associated with this transition, such as continuous financing support, availability of trained personnel, adoption of the PGx-informed prescription by the clinical staff and, ultimately, evidence of cost-effectiveness.

Cost-effectiveness of combinatorial pharmacogenomic testing for depression from the Canadian public payer perspective.

Aim: 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. Materials & methods: 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. Results: 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. Conclusion: Combinatorial PGx testing was more efficacious and less costly compared with the TAU for depression.

Cost-Effectiveness of RAS Genetic Testing Strategies in Patients With Metastatic Colorectal Cancer: A Systematic Review.

BACKGROUND: Monoclonal antibodies against epidermal growth factor receptor (EGFR) have proved beneficial for the treatment of metastatic colorectal cancer (mCRC), particularly when combined with predictive biomarkers of response. International guidelines recommend anti-EGFR therapy only for RAS (NRAS,KRAS) wild-type tumors because tumors with RAS mutations are unlikely to benefit. OBJECTIVES: We aimed to review the cost-effectiveness of RAS testing in mCRC patients before anti-EGFR therapy and to assess how well economic evaluations adhere to guidelines. METHODS: A systematic review of full economic evaluations comparing RAS testing with no testing was performed for articles published in English between 2000 and 2018. Study quality was assessed using the Quality of Health Economic Studies scale, and the British Medical Journal and the Philips checklists. RESULTS: Six economic evaluations (2 cost-effectiveness analyses, 2 cost-utility analyses, and 2 combined cost-effectiveness and cost-utility analyses) were included. All studies were of good quality and adopted the perspective of the healthcare system/payer; accordingly, only direct medical costs were considered. Four studies presented testing strategies with a favorable incremental cost-effectiveness ratio under the National Institute for Clinical Excellence (£20 000-£30 000/QALY) and the US ($50 000-$100 000/QALY) thresholds. CONCLUSIONS: Testing mCRC patients for RAS status and administering EGFR inhibitors only to patients with RAS wild-type tumors is a more cost-effective strategy than treating all patients without testing. The treatment of mCRC is becoming more personalized, which is essential to avoid inappropriate therapy and unnecessarily high healthcare costs. Future economic assessments should take into account other parameters that reflect the real world (eg, NRAS mutation analysis, toxicity of biological agents, genetic test sensitivity and specificity).

Cost-Effectiveness of Multigene Pharmacogenetic Testing in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention.

OBJECTIVE: To evaluate the cost-effectiveness of multigene testing (CYP2C19, SLCO1B1, CYP2C9, VKORC1) compared with single-gene testing (CYP2C19) and standard of care (no genotyping) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) from Medicare's perspective. METHODS: A hybrid decision tree/Markov model was developed to simulate patients post-PCI for ACS requiring antiplatelet therapy (CYP2C19 to guide antiplatelet selection), statin therapy (SLCO1B1 to guide statin selection), and anticoagulant therapy in those that develop atrial fibrillation (CYP2C9/VKORC1 to guide warfarin dose) over 12 months, 24 months, and lifetime. The primary outcome was cost (2016 US dollar) per quality-adjusted life years (QALYs) gained. Costs and QALYs were discounted at 3% per year. Probabilistic sensitivity analysis (PSA) varied input parameters (event probabilities, prescription costs, event costs, health-state utilities) to estimate changes in the cost per QALY gained. RESULTS: Base-case-discounted results indicated that the cost per QALY gained was $59 876, $33 512, and $3780 at 12 months, 24 months, and lifetime, respectively, for multigene testing compared with standard of care. Single-gene testing was dominated by multigene testing at all time horizons. PSA-discounted results indicated that, at the $50 000/QALY gained willingness-to-pay threshold, multigene testing had the highest probability of cost-effectiveness in the majority of simulations at 24 months (61%) and over the lifetime (81%). CONCLUSIONS: On the basis of projected simulations, multigene testing for Medicare patients post-PCI for ACS has a higher probability of being cost-effective over 24 months and the lifetime compared with single-gene testing and standard of care and could help optimize medication prescribing to improve patient outcomes.

Economic Outcomes Following Combinatorial Pharmacogenomic Testing for Elderly Psychiatric Patients.

OBJECTIVE: We compared economic outcomes when elderly patients with neuropsychiatric disorders received psychotropic medications guided by a combinatorial pharmacogenomic (PGx) test. METHODS: This is a subanalysis of a 1-year prospective assessment of medication cost for patients with neuropsychiatric disorders receiving combinatorial PGx testing. Pharmacy claims were used to compare per member per year (PMPY) medication cost for patients ≥65 and <65 years old when medications were congruent or incongruent with the PGx test. Polypharmacy was also assessed. RESULTS: Congruent prescribing was associated with savings of US$3497 PMPY (P < .001) for patients ≥65 years and US$2467 PMPY (P < .001) for patients <65, compared to incongruent prescribing. Congruent prescribing in patients ≥65 treated by primary care providers was associated with US$4113 PMPY (P = .026) in savings, while congruent prescribing by psychiatrists was associated with US$120 PMPY (P = .719). Congruent prescribing was also associated with one fewer neuropsychiatric medication for patients ≥65 (P = .070). CONCLUSION: Congruence with PGx testing was associated with medication cost savings in elderly patients.

Demand for Precision Medicine: A Discrete-Choice Experiment and External Validation Study.

BACKGROUND: A limited evidence base and lack of clear clinical guidelines challenge healthcare systems' adoption of precision medicine. The effect of these conditions on demand is not understood. OBJECTIVE: This research estimated the public's preferences and demand for precision medicine outcomes. METHODS: A discrete-choice experiment survey was conducted with an online sample of the US public who had recent healthcare experience. Statistical analysis was undertaken using an error components mixed logit model. The responsiveness of demand in the context of a changing evidence base was estimated through the price elasticity of demand. External validation was examined using real-world demand for the 21-gene recurrence score assay for breast cancer. RESULTS: In total, 1124 (of 1849) individuals completed the web-based survey. The most important outcomes were survival gains with statistical uncertainty, cost of testing, and medical expert agreement on changing care based on test results. The value ($US, year 2017 values) for a test where most (vs. few) experts agreed to changing treatment based on test results was $US1100 (95% confidence interval [CI] 916-1286). Respondents were willing to pay $US265 (95% CI 46-486) for a test that could result in greater certainty around life-expectancy gains. The predicted demand of the assay was 9% in 2005 and 66% in 2014, compared with real-world uptake of 7% and 71% (root-mean-square prediction error 0.11). Demand was sensitive to price (1% increase in price resulted in > 1% change in demand) when first introduced and insensitive to price (1% increase in price resulted in < 0.1% change in demand) as the evidence base became established. CONCLUSIONS: Evidence of external validity was found. Demand was weak and responsive to price in the near term because of uncertainty and an immature evidence base. Clear communication of precision medicine outcomes and uncertainty is crucial in allowing healthcare to align with individual preferences.

Cost-Effectiveness of Strategies to Personalize the Selection of P2Y12 Inhibitors in Patients with Acute Coronary Syndrome.

PURPOSE: Perform a cost-effectiveness analysis comparing strategies for selecting P2Y12 inhibitors in acute coronary syndrome (ACS). METHODS: Six strategies for selection of P2Y12 inhibitors in ACS were compared from the US healthcare system perspective: (1) clopidogrel for all (universal clopidogrel); (2) ticagrelor guided by platelet reactivity assay (PRA; clopidogrel + phenotype); (3) ticagrelor use only in CYP2C19 poor metabolizers (genotype + conservative ticagrelor); (4) ticagrelor use in both CYP2C19 intermediate and poor metabolizers (genotype + liberal ticagrelor); (5) ticagrelor use only in patients with CYP2C19 polymorphisms and clopidogrel nonresponse by PRA (genotype + phenotype); and (6) ticagrelor for all (universal ticagrelor). A decision model was developed to model major adverse cardiovascular events and bleeding during 1 year of treatment with a P2Y12 inhibitor. Model inputs were identified from the literature. Lifetime costs were adjusted to 2017 US dollars; quality-adjusted life-years (QALYs) were projected using a Markov model. The primary endpoint was the incremental cost-effectiveness compared to the next best option along the cost-effectiveness continuum. Sensitivity analyses were performed on all model inputs to assess their influence on the incremental cost-effectiveness. RESULTS: In the base case analysis, incremental cost-effectiveness ratios (ICER) for the clopidogrel + phenotype, genotype + liberal ticagrelor, and universal ticagrelor strategies were $12,119/QALY, $29,412/QALY, and $142,456/QALY, respectively. Genotype + conservative ticagrelor and genotype + phenotype were not cost-effective due to second-order dominance. Genotype + liberal ticagrelor compared to clopidogrel + phenotype demonstrated the highest acceptance (97%) at a willingness to pay (WTP) threshold of $100,000/QALY. CONCLUSION: Cost-effective strategies to personalize P2Y12 inhibition in ACS include clopidogrel +phenotype and genotype + liberal ticagrelor. Universal ticagrelor may be considered cost-effective at a higher WTP threshold ($150,000/QALY). Genotype + liberal ticagrelor exhibited the highest acceptability compared to clopidogrel + phenotype over the widest range of WTP thresholds and may be preferred.

Cost-minimization analysis of GSTP1c.313A>G genotyping for the prevention of cisplatin-induced nausea and vomiting: A Bayesian inference approach.

BACKGROUND: Chemotherapy-induced nausea and vomiting are concerning adverse events resulting from cancer treatment, and current guidelines recommend the use of neurokinin-1-selective antagonists, such as fosaprepitant, in highly emetogenic schemes. However, the implementation of this strategy may be limited by the cost of treatment. GSTP1 c.313A>G genotype was recently described as a predictor of vomiting related to high-dose cisplatin. We hypothesized that the inclusion of routine GSTP1 c.313A>G screening may be promising in financial terms, in contrast to the wide-spread use of fosaprepitant. METHODS: A cost-minimization analysis was planned to compare GSTP1 c.313A>G genotyping versus overall fosaprepitant implementation for patients with head and neck cancer under chemoradiation therapy with high-dose cisplatin. A decision analytic tree was designed, and conditional probabilities were calculated under Markov chain Monte Carlo simulations using the Metropolis-Hastings algorithm. The observed data included patients under treatment without fosaprepitant, while priors were derived from published studies. RESULTS: To introduce screening with real-time polymerase chain reaction, an initial investment of U$ 39,379.97 would be required, with an amortization cost of U$ 7,272.97 per year. The mean cost of standard therapy with fosaprepitant is U$ 243.24 per patient, and although the initial cost of routine genotyping is higher, there is a tendency of progressive minimization at a threshold of 155 patients (Credible interval-CI: 119 to 216), provided more than one sample is incorporated for simultaneous analysis. A resulting reduction of 35.83% (CI: 30.31 to 41.74%) in fosaprepitant expenditures is then expected with the implementation of GSTP1 c.313A>G genotyping. CONCLUSION: GSTP1 c.313A>G genotyping may reduce the use of preventive support for chemotherapy induced nausea and lower the overall cost of treatment. Despite the results of this simulation, randomized, interventional studies are required to control for known and unknown confounders as well as unexpected expenses.

Economic Value of Pharmacogenetic Testing for Cancer Drugs with Clinically Relevant Drug-Gene Associations: A Systematic Literature Review.

BACKGROUND: Pharmacogenetic testing can provide predictive insights about the efficacy and safety of drugs used in cancer treatment. Although many drug-gene associations have been reported in the literature, the strength of evidence supporting each association can vary significantly. Even among the subgroup of drugs classified by the PharmGKB database to have a high or moderate level of evidence, there is limited information regarding the economic value of pharmacogenetic testing. OBJECTIVES: To: (a) summarize the available pharmacoeconomic evidence assessing the value of pharmacogenetic testing for cancer drugs with clinically relevant drug-gene associations; (b) determine the quality of the studies that contain this evidence; and (c) discuss the quality of this evidence with respect to the level of evidence of the drug-gene associations. METHODS: The PharmGKB database was used to identify cancer drugs with clinically relevant drug-gene associations graded high (1A, 1B) or moderate (2A, 2B). A systematic literature review was conducted using these drugs. Ovid MEDLINE and Embase databases were searched to identify cost-effectiveness, cost-utility, or cost-minimization studies comparing pharmacogenetic testing to an alternative. Cost and effect values from every relevant comparison within the studies were extracted, and the incremental cost-effectiveness ratio (ICER) was either extracted or calculated for each comparison. Quality assessment was conducted for each study using the Quality of Health Economic Studies (QHES) instrument. Qualitative synthesis was used to summarize the data. RESULTS: The search yielded 2,191 citations, of which 35 studies met the inclusion criteria. Pharmacoeconomic studies were available for the following drugs from the PharmGKB database: fluoropyrimidine, 6-mercaptopurine, irinotecan, carboplatin, cisplatin, erlotinib, gefitinib, cetuximab, panitumumab, and trastuzumab. The studies were conducted in Asia, Europe, Canada, the United States, and Mexico and reported cost-utility, cost-effectiveness, and cost-minimization outcomes. The mean QHES score was 80 (SD = 22) for the studies of drug-gene pairs with high (1A, 1B) and moderate (2A, 2B) levels of evidence (1A = 82, 1B = 93, 2A = 71, and 2B = 74). There was variation across studies in terms of reporting. 109 relevant comparisons were identified within the studies. Of those that reported cost per life-year or cost per quality-adjusted life-year (n = 58 comparisons), pharmacogenetic testing was dominant in 21% overall and 42%, 21%, 17%, and 5% of the comparisons in Asia, Europe, Canada, and the United States, respectively. Variability was observed in the ICER values regardless of geographic region or drug. Pharmacogenetic testing was cost saving in 17 of 19 cost-minimization comparisons and was favored most frequently when compared with genetically indiscriminate strategies containing the drug of interest. CONCLUSIONS: There was mixed evidence regarding the value of pharmacogenetic testing to guide cancer treatment. For future pharmacogenomic-related economic studies, we recommend prioritizing clinically relevant drug-gene associations and greater adherence to available best practice guidelines for conducting and reporting economic evaluation studies. DISCLOSURES: No outside funding supported this review. Part of Hussain's research time was supported by a Merit Review Award (I01 BX000545), Medical Research Service, U.S. Department of Veterans Affairs. Hussain also reports personal fees from Bristol-Myers Squibb, AstraZeneca, Novartis, Bayer HealthCare Pharmaceuticals, and France Foundation, outside the submitted work. Onukwugha reports grants from Pfizer and Bayer HealthCare Pharmaceuticals, along with advisory board fees from Novo Nordisk, outside the submitted work. Faruque, Neuberger, and Noh have nothing to disclose.

A cost effective RFLP method to genotype Solute carrier organic anion 1B1 (SLCO1B1) c.1929A>C (p.Leu643Phe, rs34671512); a variant with potential effect on rosuvastatin pharmacokinetics.

OBJECTIVE: This study describes a restriction fragment polymorphism protocol for rapidly screening the polymorphism SLCO1B1 c.1929A>C in genomic DNA samples. The polymorphism SLCO1B1 c.1929A>C has been associated with increased activity resulting in increased hepatic uptake of drugs. Currently SLCO1B1 c.1929A>C is genotyped using direct sequencing techniques and 5' nuclease based assays which can be cost prohibiting in resource limited settings. The aim of this study therefore was to design and validate a cost effective RFLP for genotyping the SLCO1B1 c.1929A>C polymorphism. This study was designed to investigate the effect of the polymorphism SLCO1B1 c.1929A>C on interindividual variability in rosuvastatin pharmacokinetics in healthy volunteers of African descent. RESULTS: We describe a restriction fragment length polymorphism method to genotype SLCO1B1 c.1929A>C polymorphism using the restriction enzyme Ase1. A student's t test with Welch correction was used to establish association between the SLCO1B1 c.1929A>C variant and rosuvastatin exposure. The frequency of the SLCO1B1 c.1929C allele amongst Zimbabweans was 6%. The SLCO1B1 c.1929C allele was associated with a 75% reduction (P < 0.001) in rosuvastatin exposure when compared to individuals carrying the wild type SLCO1B1 c.1929A allele. Polymorphism c.1929A>C may therefore play a significant role in rosuvastatin response. The RFLP method is quick and cost effective.

An initial health economic evaluation of pharmacogenomic testing in patients treated for childhood cancer with anthracyclines.

BACKGROUND: Anthracyclines are a class of highly effective chemotherapeutic drugs commonly used to treat cancer patients. Anthracyclines, however, are associated with the development of serious adverse reactions, including anthracycline-induced cardiotoxicity (ACT). It is not possible, within current practice, to accurately individualize treatment to minimize risk. PROCEDURE: Recently, genetic variants have been associated with the risk of ACT in children. Building on these findings and the related genetic test, a predictive model was developed which classifies pediatric patients by their risk of developing ACT. We assessed the value of this ACT-predictive risk classification in addressing ACT. RESULTS: With current care, the estimated average lifetime cost of ACT is $8,667 per anthracycline-treated patient and approximately 7% of patients are expected to die from ACT. The projected impact of the information from the new predictive model is a 17% reduction in the risk of mortality from ACT and savings of about 6%: lives saved and lower costs. CONCLUSION: The newly identified genetic variants associated with the risk of ACT provide information that allows a more reliable prediction of the risk of ACT for a given patient and can be obtained at a very moderate cost, which is expected to lead to meaningful progress in reducing harm and costs associated with ACT.

Cost effectiveness analysis of HLA-B*58:01 genotyping prior to initiation of allopurinol for gout.

Objective: To determine whether prospective testing for HLA-B*58:01, as a strategy to prevent serious adverse reactions to allopurinol in patients with gout, is cost-effective from the perspective of the National Health Service in the UK. Methods: A systematic review and meta-analysis for the association of HLA-B*58:01 with cutaneous and hypersensitivity adverse drug reactions informed a decision analytic and Markov model to estimate lifetime costs and outcomes associated with testing vs standard care (with febuxostat prescribed for patients who test positive). Scenario analyses assessed alternative treatment assumptions and patient populations. Results: The number of patients needed to test to prevent one case of adverse drug reaction was 11 286 (95% central range (CR): 2573, 53 594). Cost and quality-adjusted life-year (QALY) gains were small, £103 (95% CR: £98, £106) and 0.0023 (95% CR: -0.0006, 0.0055), respectively, resulting in an incremental cost-effectiveness ratio (ICER) of £44 954 per QALY gained. The probability of testing being cost-effective at a threshold of £30 000 per QALY was 0.25. Reduced costs of testing or febuxostat resulted in an ICER below £30 000 per QALY gained. The ICER for patients with chronic renal insufficiency was £38 478 per QALY gained. Conclusion: Routine testing for HLA-B*58:01 in order to reduce the incidence of adverse drug reactions in patients being prescribed allopurinol for gout is unlikely to be cost-effective in the UK; however testing is expected to become cost-effective with reductions in the cost of genotyping, and with the future availability of cheaper, generic febuxostat.

Cost Evaluation of Irinotecan-Related Toxicities Associated With the UGT1A1*28 Patient Genotype.

The adoption of a preemptive UGT1A1*28 genotyping to increase irinotecan safety in clinical practice is still limited. This is the first actual study of costs associated with the management of irinotecan-related toxicities, and their association with UGT1A1*28 genotype. A retrospective analysis of the cost of toxicity management was conducted on 243 metastatic colorectal cancer patients enrolled in a clinical trial and treated with standard of care FOLFIRI (5-fluorouracil combined with irinotecan). The mean predicted cost per patient was higher for *28/*28 (€4,886), vs. *1/*1 (€812), (regression coefficient 1.79, 95% confidence interval (CI) = 1.31-2.28; P < 0.001) and for *1/*28 (€1,119) vs. *1/*1 (regression coefficient 0.32, 95% CI = 0.04-0.60; P = 0.024). This is consistent with a different grade 4 toxicity profile among the three genotypes, and a higher frequency of costly interventions like hospitalization among patients with the *28 allele. A differential toxicity management cost by *28 genotype is herein demonstrated, representing a first step towards the demonstration of the test clinical utility.

CYP2C19 LOF and GOF-Guided Antiplatelet Therapy in Patients with Acute Coronary Syndrome: A Cost-Effectiveness Analysis.

PURPOSE: This study aimed to examine the cost-effectiveness of CYP2C19 loss-of-function and gain-of-function allele guided (LOF/GOF-guided) antiplatelet therapy in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS: A life-long decision-analytic model was designed to simulate outcomes of three strategies: universal clopidogrel (75 mg daily), universal alternative P2Y12 inhibitor (prasugrel 10 mg daily or ticagrelor 90 mg twice daily), and LOF/GOF-guided therapy (LOF/GOF allele carriers receiving alternative P2Y12 inhibitor, wild-type patients receiving clopidogrel). Model outcomes included clinical event rates, quality-adjusted life-years (QALYs) gained and direct medical costs from perspective of US healthcare provider. RESULTS: Base-case analysis found nonfatal myocardial infarction (5.62%) and stent thrombosis (1.2%) to be the lowest in universal alternative P2Y12 inhibitor arm, whereas nonfatal stroke (0.72%), cardiovascular death (2.42%), and major bleeding (2.73%) were lowest in LOF/GOF-guided group. LOF/GOF-guided arm gained the highest QALYs (7.5301 QALYs) at lowest life-long cost (USD 76,450). One-way sensitivity analysis showed base-case results were subject to the hazard ratio of cardiovascular death in carriers versus non-carriers of LOF allele and hazard ratio of cardiovascular death in non-carriers of LOF allele versus general patients. In probabilistic sensitivity analysis of 10,000 Monte Carlo simulations, LOF/GOF-guided therapy, universal alternative P2Y12 inhibitor, and universal clopidogrel were the preferred strategy (willingness-to-pay threshold = 50,000 USD/QALY) in 99.07%, 0.04%, and 0.89% of time, respectively. CONCLUSIONS: Using both CYP2C19 GOF and LOF alleles to select antiplatelet therapy appears to be the preferred antiplatelet strategy over universal clopidogrel and universal alternative P2Y12 inhibitor therapy for ACS patients with PCI.

Payer view of personalized medicine.

PURPOSE: The process and methods used by payers when evaluating coverage of personalized medicine testing are described. SUMMARY: Personalized medicine encompasses a number of diagnostic tools that measure drug metabolism, genetic risk for disease development, and tumor type or markers that can guide oncology treatments. However, whole genome testing, tumor marker testing, and testing for drug metabolism are additional costs to the healthcare system. In order to justify these costs, payers and health technology assessment bodies must evaluate the individual tests or groups of tests on their own merits. In order for a test to be covered by payers, test developers must demonstrate clinical utility as measured by improved outcomes or well-informed decision-making. In the United States, payers generally focus on clinical benefit to individual patients and benefits to the healthcare system. Clinical benefits include improved outcomes. Benefits to the healthcare system are generally considered to be cost offsets, which may be due to reductions in the use of unnecessary interventions or to more efficient use of resources. Provider organizations have been assuming more responsibility and liability for healthcare costs through various risk arrangements, including accountable care organizations and patient-centered medical homes. Diagnostic tests that increase efficiency, reduce unnecessary interventions, and improve outcomes will be chosen by specialists in provider organizations. CONCLUSION: For personalized medicine approaches to be adopted and covered by health plans, the methods must be shown to be analytically and clinically valid and provide clinical utility at a reasonable level of cost-effectiveness to payers.

Cost-Effectiveness of Pharmacogenomic and Pharmacogenetic Test-Guided Personalized Therapies: A Systematic Review of the Approved Active Substances for Personalized Medicine in Germany.

BACKGROUND: The use of targeted therapies has recently increased. Pharmacogenetic tests are a useful tool to guide patient treatment and to test a response before administering medicines. Pharmacogenetic tests can predict potential drug resistance and may be used for determining genotype-based drug dosage. However, their cost-effectiveness as a diagnostic tool is often debatable. In Germany, 47 active ingredients are currently approved. A prior predictive test is required for 39 of these and is recommended for eight. The objective of this study was to review the cost-effectiveness (CE) of pharmacogenetic test-guided drug therapy and compare the application of drugs with and without prior genetic testing. METHODS: A systematic literature review was conducted to identify the CE and cost-utility of genetic tests. Studies from January 2000 until November 2015 were searched in 16 databases including Medline, Embase, and Cochrane. A quality assessment of the full-text publications was performed using the validated Quality of Health Economic Studies (QHES) instrument. RESULTS: In the majority of the included studies, the pharmacogenetic test-guided therapy represents a cost-effective/cost-saving treatment option. Only seven studies lacked a clear statement of CE or cost-savings, because of uncertainty, restriction to specific patient populations, or assumptions for comparative therapy. Moreover, the high quality of the available evidence was evaluated. CONCLUSION: Pharmacogenetic testing constitutes an opportunity to improve the CE of pharmacotherapy. The CE of targeted therapies depends on various factors including costs, prevalence of biomarkers, and test sensitivity and specificity. To guarantee the CE comparability of stratified drug therapies, national and international standards for evaluation studies should be defined.

Genetic testing and economic evaluations: a systematic review of the literature.

OBJECTIVES: To identify those studies in which economic analysis of predictive genetic and pharmacogenetic testing programs have been carried out. Since the Italian National Prevention Plan 2014-2018 foresees the implementation of genetic testing for inherited breast cancer, special attention was given to the cost-effectiveness of BRCA1/2 testing programs. METHODS: A systematic review of primary economic evaluations (EEs) of predictive genetic and pharmacogenetic testing programs and an overview of previously published systematic reviews of economic evaluations (ERs) was performed. RESULTS: Overall 128 EEs and 11 ERs were identified. The methodological quality of both EEs and ERs was good on average. Both predictive genetic and pharmacogenetic testing programs were mainly concerned with oncological diseases. Seventeen percent of genetic testing programs are cost-saving, while a further 44% of cost/QALY ratios fall under the commonly used threshold of €37,000 per QALY. For BRCA1/2 testing, only cascade genetic screening programs, targeted to close relatives of carriers, show clear evidence of cost-effectiveness. CONCLUSION: Despite some limitations, EEs and ERs are powerful tools that provide indications to policy-makers on which genetic testing programs might be introduced into health care systems and public health practice.