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Supplementary file 1. Search syntax used in literature reviewPubmed#1 MeSH in terms: carcinoma, non-small-cell lung#2 lung: ti, ab#3 (cancer* or carcin* or neoplasm* or tumour* or tumor*): ti,ab#4 (non-small or nonsmall): ti,ab#5 #2 and #3 and #4#6 nsclc: ti,ab#7 #1 or #5 or #6#8 (gefitinib or iressa): ti,ab#9 (erlotinib or tarceva): ti,ab#10 (afatinib or gilotrif): ti,ab#11 (osimertinib or tagrix): ti,ab#12 #8 or #9 or #10 or #11#13 #7 and #12#14 MeSH in terms: quality adjusted life year#15 MeSH: technology assessment, biomedical#16 MeSH: costs and cost analysis#17 MeSH: models, economic#18 cost*: ti,ab#19 economic*: ti,ab#20 life year*: ti,ab#21 #14 or #15 or #16 or #17 or #18 or #19 or #20#22 #13 and #21Cochrane Library#1 Mesh descriptor: [Carcinoma, non-small-cell lung] explore all trees#2 lung: ti,ab#3 (cancer* or carcin* or neoplasm* or tumour* or tumor*): ti,ab#4 (non-small or nonsmall): ti,ab#5 #2 and #3 and #4#6 nsclc: ti,ab#7 #1 or #5 or #6#8 (gefitinib or iressa): ti,ab#9 (erlotinib or tarceva): ti,ab#10 (afatinib or gilotrif): ti,ab#11 (osimertinib or tagrix): ti,ab#12 #8 or #9 or #10 or #11#13 #7 and #12#14 MeSH : Quality-Adjusted life years#15 MeSH: Technology Assessment, Biomedical#16 MeSH: costs and cost analysis#17 MeSH: models, economic#18 cost*: ti,ab#19 economic*: ti,ab#20 life year*: ti,ab#21 #14 or #15 or #16 or #17 or #18 or #19 or #20#22 #13 and #21Embase1 exp“nonsmallcell lung”/2 lung and (cancer$ or carcin$ or neoplasm$ or tumour$ or tumor$) and ((non-small or nonsmall) and cell)). ti,ab3 nsclc. ti,ab4 1 or 2 or 35 (gefitinib or iressa): ti,ab6 (erlotinib or tarceva): ti,ab7 (afatinib or gilotrif): ti,ab8 (osimertinib or tagrix): ti,ab9 5 or 6 or 7 or 810 4 and 911 cost$ or economic$ or life year$12 10 and 11Centre for Reviews and Dissemination Database(gefitinib OR erlotinib OR afatinib OR osimertinib)Date limited from 2000 to 2019Supplementary file 2Table A. Detailed description of included studiesTreatmentFirst authorYearPerspectiveLYGQALY’s gainedIncremental costsICER (per LYG)ICER (per QALY)Time HorizonWTP ThresholdRefafatinib vs PemCisTan PT2018Singapore healthcare payer0.140.11SG$15227SG$109172SG$1376485 years[17]afatinib vs gefitinibChouaid C20170.17€ 7,697€ 45,21110 years€70000/QALY[19]erlotinib vs afatinibTing J2015US Societal0.11$6,722 $61,809 10 years$100000/QALY[20]afatinib vs erlotinibLimwattananon2018Thai Societal perspective0.0680.015$198,961 5 years$4,500 [16]afatinib vs erlotinibLimwattananon2018Thai Healthcare perspective0.0680.015$196,662 5 years$4,500 [16]erlotinib vs platinum doublesLimwattananon2018Thai Societal perspective0.1230.193$46,783 5 years$4,500 [16]erlotinib vs platinum doublesLimwattananon2018Thai Healthcare perspective0.1230.193$45,967 5 years$4,500 [16]afatinib vs gefitinibGu X2019Chinese health care system0.2240.208$3,680 $17,693 10 years$23815/QALY[28]afatinib vs erlotinibGu X2019Chinese health care system0.1190.174$2,818 $16,197 10 years$23815/QALY[28]afatinib vs chemotherapyGu X2019Chinese health care system0.3880.382$7,930 $20,758 10 years$23815/QALY[28]afatinib vs gefitinib L858RWang H2018Chinese health care system0.3$5,552.19 $18,529.65 10 years$26,331 [32]afatinib vs gefitinib DEL19Wang H2018Chinese health care system0.27$432.70 $1,585.51 10 years$26,331 [32]gefitinib vs routine careJun Zhu20130.740.46$26,149.90 $35,260.10 $57,066.40 10 years3 times China's GDP[29]erlotinib vs pemetrexedRobert Klein MS2010US payer-0.1629$—24474no statement3 years[35]erlotinib vs chemotherapyWen F2018Chinese health care system-0.13$—22439no statement10 years$24048/year[18]erlotinib vs placeboKhan I20150.035?7089?202571?50000-?60000[21]erlotinib vs gefitinibVivian WY Lee20140.340.23$14,061 $39,431 $62,419 $102,582 [22]erlotinib vs Platinum-Based Doublet ChemotherapyWang SiYing2013Chinese health care system0.56$48,119.35 $30,455.28 $85,927.41 10 years$96,884 [24]erlotinib+DG vs DG+erlotinibChouaid C2012French health care system—0.01€—3954[25]erlotinib vs placeboVergnenègre A2012national health care payers0.28€ 11,140€ 39,783€ 50,000[26]erlotinib vs placeboVergnenègre A2012national health care payers0.28€ 13,141€ 46,931€ 50,000[26]erlotinib vs placeboVergnenègre A2012national health care payers0.28€ 7,808€ 27,885€ 40,000[26]erlotinib vs BSCWalleser Silke2012national health care payers0.39€ 7,898€ 20,711€ 50,000[27]erlotinib vs BSCWalleser Silke2012national health care payers0.39€ 9,580€ 25,124€ 50,000[27]erlotinib vs BSCWalleser Silke2012national health care payers0.39€ 8,873€ 23,271€ 50,000[27]erlotinib vs BSCWalleser Silke2012national health care payers0.39€ 8,488€ 22,261€ 50,000[27]erlotinib vs BSCWalleser Silke2012national health care payers0.39€ 8,149€ 21,368€ 50,000[27]erlotinib vs chemotherapyCarlson JJ2008national health care payers0.01Dominated2 years$50000/QALY[30]erlotinib vs gemcitabineChouaid C2013the third-party payer-0.02€—130[31]erlotinib vs chemotherapyVergnenegre A2016healthcare perspective-0.0050.117€—19363cost saving4 years€ 90,000[33]erlotinib vs chemotherapyVergnenegre A2016healthcare perspective-0.0050.117€—17672cost saving4 years€ 90,000[33]erlotinib vs chemotherapyVergnenegre A2016healthcare perspective-0.0050.117€—17331cost saving4 years€ 90,000[33]erlotinib vs placeboBradrury PA2010Canadian public health-care system0.13C$12303C$946381 year[34]gefitinib vs erlotinibM. Kimura2018JPY—69605.9/MST[15]gefitinib vs afatinibM. Kimura2018JPY122070.7/MST[15]erlotinib vs gefitinibMa Yuxiang2013Patient￥3773/month2.25 times￥15000/month[23]osimertinib vs GE-chemotherapyHongfu Cai2019Chinese medical system0.96$69,420.76 $71,954.08 10 years3 times China's GDP[36]osimertinib vs SOCEzeife DA2018Canadian public payer1.120.79$176394 CAD$162139 CAD$223,133 10 years$100000/QALY[37]osimertinib vs SOCBin Wu2018U.S. payer1.10.851$266,578 $312,903 10 years$150000/QALY[3]China public payer1.10.757$31,456 $41,512 $30000/QALYosimertinib vs gefitinibAguiar PN2018US payer0.594$231,123 10 years$180000/QALY[5]Brazilian payer$180,804 osimertinib vs erlotinibUS payer$226,527 Brazilian payer$162,329 $35000/QALYosimertinib vs afatinibUS payer$219,874 Brazilian payer$175,432 BSC: best supportive care; GE-chemotherapy: gefitinib or erlotinib first-line therapy and second-line chemotherapy; SOC: standard first-generation EGFR-TKI therapy (standard care [SOC])Table B CHEERS checklist scoreItemReferences[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][3][5]1111111111111110.50.5110.50.50.5111120.5111111111111111111111111311111111111111110.511111111400.500010.50.50.50.50.50000.510.5000.50.50.50.50.50.550.5111000.51111111111111111116011101000.51111111111111111710.50.50.511110.50.50.50.50.50.50.50.50.50.50.50.50.50.50.50.50.5801111111010111110110111119011111110111111111111011110111111111111111111111111111111111110.511111111111111111211110.510.5110.510.50.50.50.5110.50.50.510.50.50.50.5130.51110.5110.5110.510.51110.51111111114010100.50.510.51100.511110.5111111115010.510100.501011111010.501111116010000000000000001001000017010.50.50.50.50.50.500.50.50.50.50.50.50.50.50.50.50.50.50.50.50.50.5181111111111111111111111111191110.511110.51111110.50.5111011112001111110.501101111111111111210000000000000000010000000220.50.511111111110.51111111111112310.511011101110101110100100241111101001101111111001101Total122118.519.514.51917.517.512201816.51719.518.520172117.516.51818201819Table C Results of the QHES instrumentStudy12345678910111213141516ScoreKimura et al.(2018) [15]*√××√××√√√××NANA×√√39Limwattananon et al.(2018) [16]√√√√√×√√√√√√××√√81Tan et al.(2018) [17]√√√√√√√√√√√√√×√√94Wen et al.(2018) [18]√√√√××√√×××√√×√√58Chouaid et al.(2017) [19]√×√√×√√√×√√√√×√×62Ting et al.(2015) [20]√×√√√×√√√××√√×√√71Khan et al.(2015) [21]*√××√×√√√√√×NANA×√√51Lee et al.(2014) [22]√√√√×√√√√√√√√√√√91Ma et al.(2013) [23]√××√×√√×√√√√××√×56Wang et al.(2013) [24]√√×√√√√√√××√√×√√73Chouaid et al.(2012) [25]*√√×√×√××××√NANA×√√35Vergnenègre et al.(2012) [26]√√×√×√×√××√√××√√51Walleser et al.(2012) [27]√√×√√√√√×√×√××√×61Gu et al.(2019) [28]√√√√√√√√√√√√√×√√94Zhu et al.(2013) [29]√√×√√√×√√√√√×√√×77Carlson et al.(2008) [30]√√√√√×√√√√×√√√√√87Chouaid et al.(2013) [31]*√√×√×√××√×√NANA×√√44Wang et al.(2018) [32]√√√√√√√√√××√√√√√87Vergnenegre et al.(2016) [33]√√√√√√√√√√×√×√√×83Bradrury et al.(2010) [34]*√√√×√√√√√××NANA√√√71Klein et al.(2010) [35]√√×××××√×√√√√×√×54Hongfu Cai.(2019) [36]√√√×√√√×√×√√√√√×83Ezeife DA.(2018) [37]√√√×√√√√√√√√√√√√99Bin Wu.(2018) [3]√√√×√√√√√√√√√√√×96Aguiar PN.(2018) [5]√√√×√√√√√×√√√√√×90*: Modeless articleTable D Comparators of the CHEERS and QHES scoresPublicationsScoresFist AuthorYearCountryCHEERSQHESKimura 2018Japan50%39%Limwattananon2018Tailand87.50%81%Tan PT2018Singapore77.08%94%Wen F2018China81.25%58%Chouaid C2017France60.42%62%Ting Jie2015USA79.17%71%Khan I2015UK72.92%51%Vivian WY Lee2014Hong Kong72.92%91%Ma Yuxiang2013China50%56%Wang SiYing2013China83.33%73%Chouaid C2012France75%35%Vergnenègre A2012France, Germany, Italy68.75%51%Walleser Silke2012England, France, Germany, Italy, Spain70.83%61%Gu X2019China81.25%94%Jun Zhu2013China77.08%77%Carlson JJ2008USA83.33%87%Chouaid C2013France70.83%44%Wang H2018China87.5%87%Vergnenegre A2016Spain, France, Italy72.92%83%Bradrury PA2010Canada68.75%71%Robert Klein MS2010USA75%54%Hongfu Cai2019China75%83%Bin Wu2018USA, China75%96%Ezeife DA2018Canada83.33%99%Aguiar PN2018USA, Brazil79.17%90%Supplementary file 3. Overview of CHEERS and QHES questionnairesCHEERSWeightQHESWeight1. Identify the study as an economic evaluation, or use more specific terms such as "cost-effectiveness analysis" and describe the interventions compared1Was the study objective presented in a clear, specific, and measurable manner?72. Provide a structured summary of objectives, perspective, setting, methods (including study design and inputs), results (including base-case and uncertainty analyses) and conclusions1Were the perspective of the analysis (societal, third-party payer, etc.) and reasons for its selection stated?43. Provide an explicit statement of the broader context for the study. Present the study question and its relevance for health policy or practice decision1were variable estimates used in the analysis from the best available source (ie. RCT - best, Expert opinion-worst)?84. Describe characteristics of the base-case population and subgroups analyzed including why they were chosen1If estimates came from a subgroup analysis, were the groups pre-specified at the beginning of the study?15. State relevant aspects of the system(s) in which the decision(s) need(s) to be made1Was uncertainty handled by: 1) statistical analysis to address random events; 2) sensitivity analysis to cover a range of assumptions?96. Describe the perspective of the study and relate this to the costs being evaluated1Was incremental analysis performed between alternatives for resources and costs?67. Describe the interventions or strategies being compared and state why they were chosen1Was the methodology for data abstraction (including value health states and other benefits) stated?58. State the time horizon(s) over which costs and consequences are being evaluated and say why appropriate1Did the analytic horizon allow time for all relevant and important outcomes? Were benefits and costs that went beyond 1 year discounted 3-5%) and justification given for the discount rate?79. Report the choice of discount rate(s) used for costs and outcomes and say why appropriate1Was the measurement of costs appropriate and the methodology for the estimation of quantities and unit costs clearly described?810. Describe what outcomes were used as the measure(s) of benefit in the evaluation and their relevance for the type of analysis performed1Were the primary outcome measures for the economic evaluation clearly stated and were the major short term, long term and negative outcomes included?611a. Single study-based estimates: Describe fully the design features of the single effectiveness study and why the single study was a sufficient source of clinical effectiveness data1Were the health outcomes measures/scales valid and reliable? If previously tested valid and reliable measures were not available, was justification given for the measures/scales used?711b. Synthesis-based estimates: Describe fully the methods used for the identification of included studies and synthesis of clinical effectiveness data1Were the economic model (including structure), study methods and analysis, and the components of the numerator and denominator displayed in a clear transparent manner?812. If applicable, describe the population and methods used to elicit preferences for outcomes1Were the choice of economic model, main assumptions and limitations of the study stated and justified?713a. Single study-based economic evaluation: Describe approaches used to estimate resource use associated with the alternative interventions. Describe primary or secondary research methods for valuing each resource item in terms of its unit cost. Describe any adjustments made to approximate to opportunity costs1Did the author(s) explicitly discuss direction and magnitude of potential biases?613b. Model-based economic evaluation: Describe approaches and data sources used to estimate resource use associated with model health states. Describe primary or secondary research methods for valuing each resource item in terms of its unit cost. Describe any adjustments made to approximate to opportunity costs1Were the conclusions/recommendations of the study justified and based on the study results?814. Report the dates of the estimated resource quantities and unit costs. Describe methods for adjusting estimated unit costs to the year of reported costs if necessary. Describe methods for converting costs into a common currency base and the exchange rate1Was there a statement disclosing the source of funding for the study?315. Describe and give reasons for the specific type of decision-analytic model used. Providing a figure to show model structure is strongly recommended116. Describe all structural or other assumptions underpinning the decision-analytic model117. Describe all analytic methods supporting the evaluation. This could include methods for dealing with skewed, missing, or censored data; extrapolation methods; methods for pooling data; approaches to validate or make adjustments (eg half cycle corrections) to a model; and methods for handling population heterogeneity and uncertainty118. Report the values, ranges, references and if used, probability distribution for all parameters. Report reasons or sources for distributions used to represent uncertainty where appropriate. Providing a table to show the input values is strongly recommended119. For each intervention, report mean values for the main categories of estimated costs and outcomes of interest, as well as mean differences between the comparator groups. If applicable, report incremental cost-effectiveness ratios120a. Single study-based economic evaluation: Describe the effects of sampling uncertainty for estimated incremental cost, incremental effectiveness and incremental cost-effectiveness, together with the impact of methodological assumptions (such as discount rate, study perspective)120b. Model-based economic evaluation: Describe the effects on the results of uncertainty for all input parameters, and uncertainty related to the structure of the model and assumptions.121. If applicable, report differences in costs, outcomes or cost-effectiveness that can be explained by variations between subgroups of patients with different baseline characteristics or other observed variability in effects that are not reducible by more information.122. Summarize key study findings and describe how they support the conclusions reached. Discuss limitations and the generalizability of the findings and how the findings fit with current knowledge.123. Describe how the study was funded and the role of the funder in the identification, design, conduct and reporting of the analysis. Describe other nonmonetary sources of support.124. Describe any potential for conflict of interest among study contributors in accordance with journal policy. In the absence of a journal policy, we recommend authors comply with International Committee of Medical Journal Editors' recommendations.1 ................
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