The Clinical and Economic Impact of Inaccurate EGFR Mutation Tests in the Treatment of Metastatic Non-Small Cell Lung Cancer.

Advances in personalized medicine are supported by companion diagnostic molecular tests. Testing accuracy is critical for selecting patients for optimal therapy and reducing treatment-related toxicity. We assessed the clinical and economic impact of inaccurate test results between laboratory developed tests (LDTs) and a US Food and Drug Administration (FDA)-approved test for detection of epidermal growth factor receptor (EGFR) mutations. Using a hypothetical US cohort of newly diagnosed metastatic non-small cell lung cancer (NSCLC) patients and EURTAC (erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer) clinical trial data, we developed a decision analytic model to estimate the probability of misclassification with LDTs compared to a FDA-approved test. We estimated the clinical and economic impact of inaccurate test results by quantifying progression-free and quality-adjusted progression-free life years (PFLYs, QAPFLYs) lost, and costs due to incorrect treatment. The base-case analysis estimated 2.3% (n = 1422) of 60,502 newly diagnosed metastatic NSCLC patients would be misclassified with LDTs compared to 1% (n = 577) with a FDA-approved test. An average of 477 and 194 PFLYs were lost among the misclassified patients tested with LDTs compared to the FDA-approved test, respectively. Aggregate treatment costs for patients tested with LDTs were approximately $7.3 million more than with the FDA-approved test, due to higher drug and adverse event costs among patients incorrectly treated with targeted therapy or chemotherapy, respectively. Invalid tests contributed to greater probability of patient misclassification and incorrect therapy. In conclusion, risks associated with inaccurate EGFR mutation tests pose marked clinical and economic consequences to society. Utilization of molecular diagnostic tests with demonstrated accuracy could help to maximize the potential of personalized medicine.

Health Technology Assessment for Molecular Diagnostics: Practices, Challenges, and Recommendations from the Medical Devices and Diagnostics Special Interest Group.

BACKGROUND: Health technology assessments (HTAs) are increasingly used to inform coverage, access, and utilization of medical technologies including molecular diagnostics (MDx). Although MDx are used to screen patients and inform disease management and treatment decisions, there is no uniform approach to their evaluation by HTA organizations. OBJECTIVES: The International Society for Pharmacoeconomics and Outcomes Research Devices and Diagnostics Special Interest Group reviewed diagnostic-specific HTA programs and identified elements representing common and best practices. METHODS: MDx-specific HTA programs in Europe, Australia, and North America were characterized by methodology, evaluation framework, and impact. Published MDx HTAs were reviewed, and five representative case studies of test evaluations were developed: United Kingdom (National Institute for Health and Care Excellence's Diagnostics Assessment Programme, epidermal growth factor receptor tyrosine kinase mutation), United States (Palmetto's Molecular Diagnostic Services Program, OncotypeDx prostate cancer test), Germany (Institute for Quality and Efficiency in Healthcare, human papillomavirus testing), Australia (Medical Services Advisory Committee, anaplastic lymphoma kinase testing for non-small cell lung cancer), and Canada (Canadian Agency for Drugs and Technologies in Health, Rapid Response: Non-invasive Prenatal Testing). RESULTS: Overall, the few HTA programs that have MDx-specific methods do not provide clear parameters of acceptability related to clinical and analytic performance, clinical utility, and economic impact. The case studies highlight similarities and differences in evaluation approaches across HTAs in the performance metrics used (analytic and clinical validity, clinical utility), evidence requirements, and how value is measured. Not all HTAs are directly linked to reimbursement outcomes. CONCLUSIONS: To improve MDx HTAs, organizations should provide greater transparency, better communication and collaboration between industry and HTA stakeholders, clearer links between HTA and funding decisions, explicit recognition of and rationale for differential approaches to laboratory-developed versus regulatory-approved test, and clear evidence requirements.

Cost effectiveness of human papillomavirus-16/18 genotyping in cervical cancer screening.

BACKGROUND: There is limited understanding of the health economic implications of cervical screening with human papillomavirus (HPV)-16/18 genotyping. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of cervical cancer primary screening with a HPV-16/18 genotyping test which simultaneously detects 12 other high-risk HPV types. METHODS: A Markov cohort model compared four strategies: (1) cytology with reflex HPV testing for atypical squamous cells of undetermined significance (ASC-US); (2) co-testing with cytology and HPV testing; (3) HPV with reflex to cytology; and (4) HPV with 16/18 genotyping and reflex cytology (ASC-US threshold). Screening began at age 30 and was performed triennially over 40 years. Screening sensitivity and specificity values for cervical intraepithelial neoplasia (CIN) 3 were obtained from the Addressing THE Need for Advanced HPV Diagnostics (ATHENA) trial. Outcomes for a 1-year follow-up scenario wherein persistent disease was detected were estimated. Screening and cancer treatment costs were calculated from a US payer's perspective in 2013. Costs and quality-adjusted life-years (QALYs) were discounted at 3 % annually. RESULTS: Applying a US$50,000/QALY threshold, strategy (4) dominated strategies (2) and (3) by reducing costs and cancer incidence and improving QALYs, and was cost effective versus strategy (1). Accounting for persistent ≥CIN 3 at 1 year, strategy (4) was cost effective versus all other strategies. Detecting HPV-16/18 resulted in earlier diagnosis of clinically relevant ≥CIN 3 at initial screening and efficient use of follow-up resources. Outcomes were most influenced by strategy performance. CONCLUSIONS: Incorporating HPV-16/18 genotyping is cost effective and may improve detection of CIN, thereby preventing cervical cancer.

Economic and epidemiological modelling of full-length antihaemophilic factor (recombinant), plasma/albumin-free method, in previously treated patients with haemophilia A : comparison with B-domain deleted rFVIII, and value of potential viral transmission reduction due to plasma/albumin-free status.

OBJECTIVES: To the extent that current recombinant clotting factor concentrates contain even trace amounts of human or animal protein, there is continuing potential for transmission of nonenveloped viruses, including hepatitis A, and parvovirus, and the theoretical potential for transmission of relatively unknown agents, such as prions (Creutzfeldt-Jakob disease, or its variant). Full-length antihaemophilic factor (recombinant), plasma/albumin-free method (rAHF-PFM; Advate), represents a novel pharmacotherapeutic option for the management of haemophilia A. This investigation was designed to discern: (i) the efficacy-based use pattern (International Units [IUs]) of rAHF-PFM versus B-domain deleted rFVIII (BDDrFVIII; ReFacto) required to resolve a bleeding episode (event) among previously treated patients with haemophilia A employing on-demand treatment; (ii) the health service expenditure pattern (percentage differential; payor's perspective) associated with use of rAHF-PFM versus BDDrFVIII among previously treated patients with haemophilia A employing on-demand treatment; and (iii) the fiscal utility attributable to the plasma/albumin-free status of rAHF-PFM under the assumed emergence of a novel and infectious blood (plasma)-borne virus. MATERIALS AND METHODS: Data stemming from phase II/phase III clinical trials of rAHF-PFM, together with published literature on BDDrFVIII, afforded calculation of the probability of occurrence for specific endpoints of interest (e.g. non-response to first infusion). Monte Carlo simulation, a decision-analytical framework parameterised with stochastic (random) and deterministic (fixed) components (10 000 iterations per month [or year] of age examined [3, 6, 9 months; years 1 through 19; and years 20, 30, 40, 50, 60, 70 and 80]) was used to compare: (i) the efficacy-based use pattern by treatment option; and (ii) the health service utilisation-based expenditure pattern by treatment option, accounting for the need for subsequent infusion(s), and potential complications (use of services) stemming from failure of the initial infusion (five scenarios). Theoretical and direct modelling methods for assessing the fiscal utility attributable to the plasma/albumin-free status of rAHF-PFM under the assumed emergence of a novel and infectious blood (plasma)-borne virus were developed. Assumptions included: (i) a low population infection rate (<5%); (ii) annual health service expenditures equivalent to 5% of that observed with HIV/AIDS; and (iii) the number of bleeding events experienced per year were 6, 9 or 12. RESULTS: Monte Carlo simulation-replicated simulations per year of age examined revealed: (i) use of rAHF-PFM resulted in a 12.20% median reduction in the number of IUs required to resolve a bleeding episode (event) relative to BDDrFVIII (p < 0.05); and (ii) a health service utilisation-based savings [primary care; hospital] (p < 0.05; range 13.74-39.34% [dependent on intensity (sequencing) of care required]) with rAHF-PFM relative to BDDrFVIII. The overall scenario-weighted health service utilisation-based savings was 16.94% (p < 0.05). Under the assumption of the emergence of a novel and infectious blood (plasma)-borne virus, deterministic models for persons weighing 20 kg, 50 kg and 80 kg all revealed a savings potential ($US per IU) with use of rAHF-PFM relative to use of a non-plasma/albumin-free product. CONCLUSION: Use of rAHF-PFM in on-demand management of haemophilia A offers enhanced patient safety and represents a fiscally prudent therapeutic strategy.

A study of influenza and influenza-related complications among children in a large US health insurance plan database.

BACKGROUND: Influenza places a substantial burden on the affected individual and society. While there are data available on the overall occurrence of influenza in children, less information is available on the differential impact of influenza on healthcare for previously healthy children and those at high risk of developing influenza-related complications. OBJECTIVE: To compare the frequency of influenza-related complications in healthy and 'at-risk' children, and quantify the associated use of medical resources and costs. DESIGN: Data were obtained from a large US-based health insurance plan database. MAIN OUTCOME MEASURES AND RESULTS: A total of 23 188 health insurance claims with an influenza diagnosis were identified over the 3-year period 1995-1997 (3 247 834 patient-years). Influenza-related complications were observed in approximately a quarter of the total diagnosed cases, with younger children (0-4 years of age) at substantially greater risk. 'At-risk' children were more likely to develop influenza-related complications than otherwise healthy children. The greatest difference in incidence rate in the 0-4 year age group was for asthma (incidence rate ratio 8.7, 95% CI 5.2-14.4), and in the 5-14 year age group for asthma (incidence rate ratio 8.5, 95% CI 5.2-13.7) and acute sinusitis (incidence rate ratio 2.7, 95% CI 1.2-5.4). The average direct medical costs of influenza in children under 15 years with complications were more than 3.5 times higher than those without. CONCLUSIONS: Measures to prevent and treat influenza-related complications are certainly warranted for at-risk children, although the elevated incidence rates for several common complications even among healthy children should prompt consideration of these measures for all children.