# Everolimus · advanced hepatocellular carcinoma after sorafenib · evidence check for improved overall survival Verdict 2938 · Evidence Check Stored-material review date: Not recorded Original evidence cut-off: 2026-08-26 Review-criteria version: 1.0 Public page/material preparation date: 2026-10-11 Clinical papers were not read directly; existing review summaries were checked. No new clinical-literature search was performed. Unverified does not mean that research is absent or that there is no effect. ## Assessment scope - Population: Child-Pugh A advanced hepatocellular carcinoma after sorafenib failure or intolerance; original selected population at 121 centers in 17 countries - Ingredient, formulation and route: Original trial intervention of everolimus plus best supportive care - Dose: Historical research exposure of 7.5 mg/day; nominal or actual exposure, formulation and route details remain unverified; not dosing instructions - Comparator: Original matching-placebo record; actual group-specific supportive or subsequent treatment remains unverified - Measured outcome: Primary overall survival; distinguish median OS, death counts and HR - Duration: Original median OS 7.6/7.3 months and TTP 3.0/2.6 months are endpoint time values; total follow-up or exposure and DCR assessment times remain unverified - Questions outside this scope: Transferring DCR or TTP into OS benefit; Certifying non-significant OS as zero effect, equivalence or safety; Extension to other Child-Pugh classes, treatment lines, doses, products or current treatment strategies; Medication, treatment-choice, substitution or discontinuation instructions; Adding the same two sheets or endpoints as new independent trials or participants ## Checklist items ### N01 · Which existing question is being transferred to this sheet? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The selected existing question is ‘Improved overall survival’; the question and existing verdict record are distinguished. The parent overall-survival draft's context is preserved in the complete copy, and other subclaims are not separate clinical trials. - Why unverified: Some information for this item exists in the preserved summary and has been linked. The original candidate's boundary-review pending state is historical; review of the existing question boundary remains incomplete. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: The original candidate's boundary-review pending state is historical; review of the existing question boundary remains incomplete. - Required materials and conditions: Preserved draft distinguishing the existing question, record location and parent and sibling scopes - Materials to obtain first: Preserved draft distinguishing the existing question, record location and parent and sibling scopes - Further research: Proposal: An updated draft retaining the original question and record relationship if additional reports for the same question are supplied - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Which existing question is being transferred to this sheet" and link them to original locations. The original candidate's boundary-review pending state is historical; review of the existing question boundary remains incomplete. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Which existing question is being transferred to this sheet. - Application exceptions: The original candidate's boundary-review pending state is historical; review of the existing question boundary remains incomplete. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: The original candidate's boundary-review pending state is historical; review of the existing question boundary remains incomplete. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C01. - Related sources: R01 ### N02 · How are the subclaim grade and note distinguished from the parent score and axes? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The selected subclaim grade is D, with the note ‘The result was null, HR 1.05, P=.68.’ Subclaim score, status and axes fields are absent; parent grade D, score 34 and safety Caution are parent history. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Direct values for the subclaim score, status and axes are absent from the original. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Direct values for the subclaim score, status and axes are absent from the original. - Required materials and conditions: Separate locations for the selected subclaim wording and parent verdict history - Materials to obtain first: Separate locations for the selected subclaim wording and parent verdict history - Further research: Proposal: A preserved copy separating complete original wording from the change event when the selected subclaim verdict itself is corrected - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "How are the subclaim grade and note distinguished from the parent score and axes" and link them to original locations. Direct values for the subclaim score, status and axes are absent from the original. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: How are the subclaim grade and note distinguished from the parent score and axes. - Application exceptions: Do not uniformly change subclaim C or D to D or inherit the parent's 34 points as a subclaim score. - Remaining uncertainty: Direct values for the subclaim score, status and axes are absent from the original. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C01, C09. - Related sources: R01 ### N03 · Do the two sheets concern the same EVOLVE-1 report, trial and population? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The parent's evidence and citation lists each contain 1 record linking Zhu AX et al. 2014 EVOLVE-1, PMID 25058218 and NCT01035229. The two existing outcomes, time to progression and safety share this preserved report's context. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Other report versions, follow-up results and current unique study or participant totals have not been established. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Other report versions, follow-up results and current unique study or participant totals have not been established. - Required materials and conditions: Relationship table for bibliography, registration, shared cohort and individual outcomes - Materials to obtain first: Relationship table for bibliography, registration, shared cohort and individual outcomes - Further research: Proposal: An outcome-specific material list preserving the same-trial relationship when original or follow-up reports are supplied - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Do the two sheets concern the same EVOLVE-1 report, trial and population" and link them to original locations. Other report versions, follow-up results and current unique study or participant totals have not been established. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Do the two sheets concern the same EVOLVE-1 report, trial and population. - Application exceptions: Do not add the two sheets' 546 participants, 362/184 or two questions as independent replications or new participants. - Remaining uncertainty: Other report versions, follow-up results and current unique study or participant totals have not been established. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C02, E07, H07. - Related sources: R01 ### N04 · What materials were actually read during this work? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The specified complete parent verdict summary was read for production and the original preserved. External articles, abstracts, registration and plans remain unread and access was not attempted. The PubMed URL is the existing citation link. - Why unverified: Some information for this item exists in the preserved summary and has been linked. External availability, acquisition, reading and link operation were not verified during this work. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: External availability, acquisition, reading and link operation were not verified during this work. - Required materials and conditions: Material records separating the preserved summary from external original materials - Materials to obtain first: Material records separating the preserved summary from external original materials - Further research: Proposal: Material records distinguishing reading level and dates when follow-up work that actually obtains new materials is authorized - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What materials were actually read during this work" and link them to original locations. External availability, acquisition, reading and link operation were not verified during this work. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What materials were actually read during this work. - Application exceptions: Summary reading is not labeled as reading clinical original materials, and no access attempt is not converted into access failure. - Remaining uncertainty: External availability, acquisition, reading and link operation were not verified during this work. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C03. - Related sources: R01 ### N05 · What is the selected population and previous sorafenib-treatment scope? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: EVOLVE-1 concerned Child-Pugh A patients with advanced hepatocellular carcinoma who failed or could not tolerate sorafenib. This scope is not transferred to all other liver diseases or treatment lines. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Age, sex, etiology, baseline tumor burden, specific inclusion or exclusion criteria and the respective proportions of failure and intolerance are absent from the preserved summary. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Age, sex, etiology, baseline tumor burden, specific inclusion or exclusion criteria and the respective proportions of failure and intolerance are absent from the preserved summary. - Required materials and conditions: Recruitment criteria, baseline tables, previous treatment and distinctions between failure and intolerance - Materials to obtain first: Recruitment criteria, baseline tables, previous treatment and distinctions between failure and intolerance - Further research: Proposal: Comparative materials specifying prespecified population-specific outcomes and scope in the same indication - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What is the selected population and previous sorafenib-treatment scope" and link them to original locations. Age, sex, etiology, baseline tumor burden, specific inclusion or exclusion criteria and the respective proportions of failure and intolerance are absent from the preserved summary. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What is the selected population and previous sorafenib-treatment scope. - Application exceptions: Age, sex, etiology, baseline tumor burden, specific inclusion or exclusion criteria and the respective proportions of failure and intolerance are absent from the preserved summary. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Age, sex, etiology, baseline tumor burden, specific inclusion or exclusion criteria and the respective proportions of failure and intolerance are absent from the preserved summary. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C04, E08. - Related sources: R01 ### N06 · How are 17 countries, 121 centers and participant distributions related? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The preserved design is a randomized, double-blind, placebo-controlled phase 3 trial at 121 centers in 17 countries. Center and country counts are not participant or independent-trial counts. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Recruitment counts by country or center, baseline balance, regional outcomes and follow-up differences remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Recruitment counts by country or center, baseline balance, regional outcomes and follow-up differences remain unverified. - Required materials and conditions: Center, country and recruitment flow and baseline distribution tables - Materials to obtain first: Center, country and recruitment flow and baseline distribution tables - Further research: Proposal: Link prespecified subgroup materials on regional or selection differences as outcomes within the same trial when available - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "How are 17 countries, 121 centers and participant distributions related" and link them to original locations. Recruitment counts by country or center, baseline balance, regional outcomes and follow-up differences remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: How are 17 countries, 121 centers and participant distributions related. - Application exceptions: Recruitment counts by country or center, baseline balance, regional outcomes and follow-up differences remain unverified. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Recruitment counts by country or center, baseline balance, regional outcomes and follow-up differences remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C04, E01, E07. - Related sources: R01 ### N07 · What was the actual everolimus exposure and dose scope? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The original study compared everolimus 7.5 mg/day plus best supportive care with placebo. This value is recorded only as historical research exposure, not medication or treatment instructions. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Original formulation, detailed administration route, exposure duration, actual cumulative dose, dose reduction, discontinuation and adherence materials remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Original formulation, detailed administration route, exposure duration, actual cumulative dose, dose reduction, discontinuation and adherence materials remain unverified. - Required materials and conditions: Study product or formulation and nominal or actual exposure and change materials - Materials to obtain first: Study product or formulation and nominal or actual exposure and change materials - Further research: Proposal: Research materials distinguishing exposure-specific results within the trial conditions when supplied - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What was the actual everolimus exposure and dose scope" and link them to original locations. Original formulation, detailed administration route, exposure duration, actual cumulative dose, dose reduction, discontinuation and adherence materials remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What was the actual everolimus exposure and dose scope. - Application exceptions: Nominal 7.5 mg/day is not converted into an individual dose or effects of other formulations or doses. - Remaining uncertainty: Original formulation, detailed administration route, exposure duration, actual cumulative dose, dose reduction, discontinuation and adherence materials remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C05, E02, E08. - Related sources: R01 ### N08 · How are placebo, supportive care and subsequent treatments distinguished? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The preserved summary records matching placebo and everolimus plus best supportive care as study conditions. Specific control-group and group-specific supportive care remain a separate scope to document. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Actual supportive-care balance, subsequent anticancer or rescue therapy, departures, crossover and analysis handling remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Actual supportive-care balance, subsequent anticancer or rescue therapy, departures, crossover and analysis handling remain unverified. - Required materials and conditions: Group-specific concomitant and subsequent treatments, departures and analysis handling tables - Materials to obtain first: Group-specific concomitant and subsequent treatments, departures and analysis handling tables - Further research: Proposal: Follow-up materials linking subsequent-treatment or crossover information to the original randomized comparison - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "How are placebo, supportive care and subsequent treatments distinguished" and link them to original locations. Actual supportive-care balance, subsequent anticancer or rescue therapy, departures, crossover and analysis handling remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: How are placebo, supportive care and subsequent treatments distinguished. - Application exceptions: Matching placebo alone does not establish that all concomitant and subsequent treatments were identical. - Remaining uncertainty: Actual supportive-care balance, subsequent anticancer or rescue therapy, departures, crossover and analysis handling remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C05, E02. - Related sources: R01 ### N09 · What were randomization, full-analysis and group denominators? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Preserve the recorded sample of 546 randomized and analyzed participants: 362 everolimus versus 184 placebo. The existing research description records 2:1 allocation and inclusion of everyone in the full analysis population. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Endpoint-specific measurable, completed, followed and safety-analysis denominators require separate tables. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Endpoint-specific measurable, completed, followed and safety-analysis denominators require separate tables. - Required materials and conditions: Allocation-to-exposure-to-analysis flow, endpoint denominators and exclusion reasons - Materials to obtain first: Allocation-to-exposure-to-analysis flow, endpoint denominators and exclusion reasons - Further research: Proposal: Original reports distinguishing analysis populations for each outcome within the same allocated population - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What were randomization, full-analysis and group denominators" and link them to original locations. Endpoint-specific measurable, completed, followed and safety-analysis denominators require separate tables. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What were randomization, full-analysis and group denominators. - Application exceptions: The full-analysis description is not extended to complete observation of all imaging or safety data or current ITT certification. - Remaining uncertainty: Endpoint-specific measurable, completed, followed and safety-analysis denominators require separate tables. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C07, E04. - Related sources: R01 ### N10 · What is the scope of handling missingness, follow-up loss and discontinuation? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Preserve the original summary stating that all 546 participants were included in the full analysis population. Death, progression, medication discontinuation and loss to follow-up are different events. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Group-specific follow-up loss, administrative censoring, missingness reasons, sensitivity analyses and observation after discontinuation are absent from the original summary. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Group-specific follow-up loss, administrative censoring, missingness reasons, sensitivity analyses and observation after discontinuation are absent from the original summary. - Required materials and conditions: Endpoint-specific missingness or censoring, discontinuation, analysis plans and sensitivity results - Materials to obtain first: Endpoint-specific missingness or censoring, discontinuation, analysis plans and sensitivity results - Further research: Proposal: Supplementary reports of missingness or follow-up materials based on actual flow and original analysis assumptions - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What is the scope of handling missingness, follow-up loss and discontinuation" and link them to original locations. Group-specific follow-up loss, administrative censoring, missingness reasons, sensitivity analyses and observation after discontinuation are absent from the original summary. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What is the scope of handling missingness, follow-up loss and discontinuation. - Application exceptions: Group-specific follow-up loss, administrative censoring, missingness reasons, sensitivity analyses and observation after discontinuation are absent from the original summary. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Group-specific follow-up loss, administrative censoring, missingness reasons, sensitivity analyses and observation after discontinuation are absent from the original summary. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C07, E04, H06. - Related sources: R01 ### N11 · What original record describes the allocation process? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The existing research description preserves the quotation that participants were registered using an interactive voice- or web-response system and randomized. The 2:1 allocation is the group allocation ratio within the same trial. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Original details of random-number generation, stratification variables, sequence access, operational roles and baseline balance remain externally unread. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Original details of random-number generation, stratification variables, sequence access, operational roles and baseline balance remain externally unread. - Required materials and conditions: Original locations of allocation or concealment procedures and baseline tables - Materials to obtain first: Original locations of allocation or concealment procedures and baseline tables - Further research: Proposal: Materials linking allocation history and original analysis when registration, protocols or reports are actually supplied - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What original record describes the allocation process" and link them to original locations. Original details of random-number generation, stratification variables, sequence access, operational roles and baseline balance remain externally unread. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What original record describes the allocation process. - Application exceptions: Original details of random-number generation, stratification variables, sequence access, operational roles and baseline balance remain externally unread. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Original details of random-number generation, stratification variables, sequence access, operational roles and baseline balance remain externally unread. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions E01. - Related sources: R01 ### N12 · Whom and which procedures does the double-blinding record concern? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Preserve the original records ‘randomized, double-blind’ and ‘matching placebo’. A blinding description is not automatically identical to current outcome-specific measurement procedures. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Specific blinding of participants, clinicians, outcome assessors and statisticians, unblinding, success and imaging interpretation remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Specific blinding of participants, clinicians, outcome assessors and statisticians, unblinding, success and imaging interpretation remain unverified. - Required materials and conditions: Blinded parties, maintenance or unblinding and endpoint-specific assessment procedures - Materials to obtain first: Blinded parties, maintenance or unblinding and endpoint-specific assessment procedures - Further research: Proposal: Distinguish blinding scope through original materials reporting actual assessment conditions for each outcome - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Whom and which procedures does the double-blinding record concern" and link them to original locations. Specific blinding of participants, clinicians, outcome assessors and statisticians, unblinding, success and imaging interpretation remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Whom and which procedures does the double-blinding record concern. - Application exceptions: Specific blinding of participants, clinicians, outcome assessors and statisticians, unblinding, success and imaging interpretation remain unverified. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Specific blinding of participants, clinicians, outcome assessors and statisticians, unblinding, success and imaging interpretation remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions E01, E03. - Related sources: R01 ### N13 · Are randomized design and current bias judgments separated? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The parent historically recorded a large randomized trial with a hard endpoint and four B0 evidence items. No RoB2 assessment or new bias grade is performed during this production work. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Official outcome-specific risk assessment and original-document comparison remain within the user's review scope. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Official outcome-specific risk assessment and original-document comparison remain within the user's review scope. - Required materials and conditions: Original details of design, allocation, missingness, measurement and selective reporting - Materials to obtain first: Original details of design, allocation, missingness, measurement and selective reporting - Further research: Proposal: An updated draft documenting outcome-specific design information when additional original materials are supplied - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Are randomized design and current bias judgments separated" and link them to original locations. Official outcome-specific risk assessment and original-document comparison remain within the user's review scope. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Are randomized design and current bias judgments separated. - Application exceptions: Parent B0 and the true large-hard-endpoint-RCT marker are not automatically inherited as fulfillment of conditions for both subclaims. - Remaining uncertainty: Official outcome-specific risk assessment and original-document comparison remain within the user's review scope. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions E01, E03, E04, E06. - Related sources: R01 ### N14 · What is the effect of interest for adherence, treatment changes and the randomized comparison? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Preserved values concern the randomized everolimus-versus-placebo comparison. Nominal research exposure is distinguished from actual medication use and maintenance effects. - Why unverified: Some information for this item exists in the preserved summary and has been linked. PP or adherence effects, actual dose intensity and group-specific treatment-change or subsequent-treatment analyses remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: PP or adherence effects, actual dose intensity and group-specific treatment-change or subsequent-treatment analyses remain unverified. - Required materials and conditions: Effect of interest, analysis population and handling of adherence or treatment changes - Materials to obtain first: Effect of interest, analysis population and handling of adherence or treatment changes - Further research: Proposal: Supplementary reports from the same trial explicitly linking analyses different from the randomized comparison - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What is the effect of interest for adherence, treatment changes and the randomized comparison" and link them to original locations. PP or adherence effects, actual dose intensity and group-specific treatment-change or subsequent-treatment analyses remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What is the effect of interest for adherence, treatment changes and the randomized comparison. - Application exceptions: PP or adherence effects, actual dose intensity and group-specific treatment-change or subsequent-treatment analyses remain unverified. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: PP or adherence effects, actual dose intensity and group-specific treatment-change or subsequent-treatment analyses remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions E02, E04. - Related sources: R01 ### N15 · Do outcome collection and assessment procedures fit the actual endpoints? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Overall survival, disease control and time to progression are different measured outcomes within the same trial. The double-blind design is preserved, but outcome-specific interpretation or ascertainment methods are separately required. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Death ascertainment routes, imaging criteria, assessment schedules, central review, assessor blinding and repeated assessments remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Death ascertainment routes, imaging criteria, assessment schedules, central review, assessor blinding and repeated assessments remain unverified. - Required materials and conditions: Endpoint-specific definitions, methods, assessors, schedules and missing measurements - Materials to obtain first: Endpoint-specific definitions, methods, assessors, schedules and missing measurements - Further research: Proposal: Original reports or appendices linking actual endpoint measurement procedures to reported values - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Do outcome collection and assessment procedures fit the actual endpoints" and link them to original locations. Death ascertainment routes, imaging criteria, assessment schedules, central review, assessor blinding and repeated assessments remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Do outcome collection and assessment procedures fit the actual endpoints. - Application exceptions: Death ascertainment routes, imaging criteria, assessment schedules, central review, assessor blinding and repeated assessments remain unverified. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Death ascertainment routes, imaging criteria, assessment schedules, central review, assessor blinding and repeated assessments remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C06, E03. - Related sources: R01 ### N16 · Can analysis models, adjustment and between-group or within-group outcomes be distinguished? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Preserved numbers are between-group HR and P comparisons and group-specific medians or proportions. Group-specific medians or proportions are not written as within-group changes. - Why unverified: Some information for this item exists in the preserved summary and has been linked. HR models, adjustment variables, stratification, assumptions, proportion-comparison tests and sensitivity analyses remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: HR models, adjustment variables, stratification, assumptions, proportion-comparison tests and sensitivity analyses remain unverified. - Required materials and conditions: Estimate definitions in statistical methods, SAP and original outcome tables - Materials to obtain first: Estimate definitions in statistical methods, SAP and original outcome tables - Further research: Proposal: Additional materials publishing original models and distinguishing adjusted from unadjusted outcomes - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Can analysis models, adjustment and between-group or within-group outcomes be distinguished" and link them to original locations. HR models, adjustment variables, stratification, assumptions, proportion-comparison tests and sensitivity analyses remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Can analysis models, adjustment and between-group or within-group outcomes be distinguished. - Application exceptions: HR models, adjustment variables, stratification, assumptions, proportion-comparison tests and sensitivity analyses remain unverified. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: HR models, adjustment variables, stratification, assumptions, proportion-comparison tests and sensitivity analyses remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C06, E04, E05. - Related sources: R01 ### N17 · What is the history of prespecified primary overall survival and registration? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Preserve the existing research description's quotation ‘The primary end point was overall survival’ and recorded agreement with NCT01035229. The registration number is the original identifier in the existing evidence list. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Current registration documents, change history, protocol and SAP were not read or compared. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Current registration documents, change history, protocol and SAP were not read or compared. - Required materials and conditions: Original locations of primary endpoints, analyses and times in registration versions, protocol, SAP and report - Materials to obtain first: Original locations of primary endpoints, analyses and times in registration versions, protocol, SAP and report - Further research: Proposal: A linked draft distinguishing prespecification and reasons for changes in follow-up work that receives actual plan materials - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What is the history of prespecified primary overall survival and registration" and link them to original locations. Current registration documents, change history, protocol and SAP were not read or compared. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What is the history of prespecified primary overall survival and registration. - Application exceptions: Original registration-agreement wording is not labeled as current registration reading or prespecification certification. - Remaining uncertainty: Current registration documents, change history, protocol and SAP were not read or compared. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions E06, C09. - Related sources: R01 ### N18 · What is the scope of secondary positivity after primary failure and multiplicity? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The existing reader answer and counterview record positive secondary disease control after failure of primary overall survival. Preserve the parent's primary-failed-secondary-positive marker as true. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Complete secondary endpoint lists, hierarchical testing, multiplicity adjustment, prespecified confirmatory status and changes remain externally unread. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Complete secondary endpoint lists, hierarchical testing, multiplicity adjustment, prespecified confirmatory status and changes remain externally unread. - Required materials and conditions: Complete primary or secondary outcome lists and multiplicity plans in protocol, SAP and registration - Materials to obtain first: Complete primary or secondary outcome lists and multiplicity plans in protocol, SAP and registration - Further research: Proposal: A draft distinguishing the statistical scope of secondary outcomes when plan and result materials from the same trial are supplied - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What is the scope of secondary positivity after primary failure and multiplicity" and link them to original locations. Complete secondary endpoint lists, hierarchical testing, multiplicity adjustment, prespecified confirmatory status and changes remain externally unread. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What is the scope of secondary positivity after primary failure and multiplicity. - Application exceptions: P=.01 is not automatically promoted into confirmatory success, survival benefit or a new grade. - Remaining uncertainty: Complete secondary endpoint lists, hierarchical testing, multiplicity adjustment, prespecified confirmatory status and changes remain externally unread. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions E06, C08, E09. - Related sources: R01 ### N19 · Are direct materials available for subgroups, responders, dose and persistence questions? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The parent's population is Child-Pugh A after sorafenib failure or intolerance, and research exposure is 7.5 mg/day. Molecular selection, responders and other-dose or persistence effects are not separately supplied. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Prespecified subgroups, interactions, molecular markers, direct dose comparisons and outcomes after treatment discontinuation remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Prespecified subgroups, interactions, molecular markers, direct dose comparisons and outcomes after treatment discontinuation remain unverified. - Required materials and conditions: Prespecified subgroup, interaction and exposure-specific original outcomes and plans - Materials to obtain first: Prespecified subgroup, interaction and exposure-specific original outcomes and plans - Further research: Proposal: Link additional research materials with explicit population or exposure, distinguishing the same from separate study families - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Are direct materials available for subgroups, responders, dose and persistence questions" and link them to original locations. Prespecified subgroups, interactions, molecular markers, direct dose comparisons and outcomes after treatment discontinuation remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Are direct materials available for subgroups, responders, dose and persistence questions. - Application exceptions: Prespecified subgroups, interactions, molecular markers, direct dose comparisons and outcomes after treatment discontinuation remain unverified. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Prespecified subgroups, interactions, molecular markers, direct dose comparisons and outcomes after treatment discontinuation remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions E08, E07. - Related sources: R01 ### N20 · Can this scope be extended to other liver function, treatment lines or long-term harms? Verification status: Unverified Reading scope: Summary read; external materials not read - Current findings: The current draft is limited to historical EVOLVE-1: Child-Pugh A advanced hepatocellular carcinoma after sorafenib. Other liver function, populations, treatment lines and current strategies are outside this direct result's scope. - Why unverified: Direct details of this condition were not verified within the current preserved-summary and externally unread scope. No new search was conducted for direct materials on other populations or exposures, longer observation, rare harms or current treatment combinations. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: No new search was conducted for direct materials on other populations or exposures, longer observation, rare harms or current treatment combinations. - Required materials and conditions: Direct comparisons and safety materials by extended population, exposure and duration - Materials to obtain first: Direct comparisons and safety materials by extended population, exposure and duration - Further research: Proposal: Link materials for separate indications or durations with explicit differences in applicability from the existing results when supplied - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Can this scope be extended to other liver function, treatment lines or long-term harms" and link them to original locations. No new search was conducted for direct materials on other populations or exposures, longer observation, rare harms or current treatment combinations. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Can this scope be extended to other liver function, treatment lines or long-term harms. - Application exceptions: No new search was conducted for direct materials on other populations or exposures, longer observation, rare harms or current treatment combinations. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: No new search was conducted for direct materials on other populations or exposures, longer observation, rare harms or current treatment combinations. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C04, E08, H08. - Related sources: R01 ### N21 · What are the selected overall-survival definition, hierarchy and time origin? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The selected question is improved overall survival, and the existing evidence-list endpoint is primary overall survival. Disease control, time to progression and stomatitis are separate outcomes. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Time origin, death ascertainment, administrative closure, planned event counts and follow-up duration details remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Time origin, death ascertainment, administrative closure, planned event counts and follow-up duration details remain unverified. - Required materials and conditions: OS definition, time origin, death ascertainment and planned or final follow-up materials - Materials to obtain first: OS definition, time origin, death ascertainment and planned or final follow-up materials - Further research: Proposal: Original materials linking OS definitions, analyses and follow-up reports from the same trial - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What are the selected overall-survival definition, hierarchy and time origin" and link them to original locations. Time origin, death ascertainment, administrative closure, planned event counts and follow-up duration details remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What are the selected overall-survival definition, hierarchy and time origin. - Application exceptions: Time origin, death ascertainment, administrative closure, planned event counts and follow-up duration details remain unverified. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Time origin, death ascertainment, administrative closure, planned event counts and follow-up duration details remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C06, E06, E09. - Related sources: R01 ### N22 · What do median OS values of 7.6 versus 7.3 months represent? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Median overall survival for everolimus versus placebo was 7.6 versus 7.3 months. These are group-specific median survival times, not total follow-up duration or within-group improvement. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Median CIs, estimation methods, data cutoff and total follow-up duration are absent from the preserved summary. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Median CIs, estimation methods, data cutoff and total follow-up duration are absent from the preserved summary. - Required materials and conditions: Group-specific median survival, CI, survival curves and data cutoff - Materials to obtain first: Group-specific median survival, CI, survival curves and data cutoff - Further research: Proposal: Original OS tables publishing medians alongside between-group estimates - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What do median OS values of 7.6 versus 7.3 months represent" and link them to original locations. Median CIs, estimation methods, data cutoff and total follow-up duration are absent from the preserved summary. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What do median OS values of 7.6 versus 7.3 months represent. - Application exceptions: Do not subtract the two medians to create a new benefit or harm duration or present them as study follow-up duration. - Remaining uncertainty: Median CIs, estimation methods, data cutoff and total follow-up duration are absent from the preserved summary. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C06, E05. - Related sources: R01 ### N23 · What is the original direction of the OS HR, 95% CI and P? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Preserve OS HR 1.05 (95% CI 0.86~1.27), P=.68. The original subclaim note and parent describe a null result for improved overall survival. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Complete original details of HR models, adjustment, stratification, assumption checks and prespecified judgment criteria remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Complete original details of HR models, adjustment, stratification, assumption checks and prespecified judgment criteria remain unverified. - Required materials and conditions: Original OS tables, SAP, HR analysis methods and intervals - Materials to obtain first: Original OS tables, SAP, HR analysis methods and intervals - Further research: Proposal: Additional reports linking actual HR analysis definitions, plans and outcomes - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What is the original direction of the OS HR, 95% CI and P" and link them to original locations. Complete original details of HR models, adjustment, stratification, assumption checks and prespecified judgment criteria remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What is the original direction of the OS HR, 95% CI and P. - Application exceptions: HR is not converted into a survival proportion, RR or change in mean or median survival. - Remaining uncertainty: Complete original details of HR models, adjustment, stratification, assumption checks and prespecified judgment criteria remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C06, C07, C08, E04, E05. - Related sources: R01 ### N24 · What are the death events, participant denominators and original proportions? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The existing reader answer records deaths of 303/362 (83.7%) versus 151/184 (82.1%). Preserve group-specific events, denominators and original proportions together. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Cause-specific death categories, censored counts, populations at risk by time and completeness of death data remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Cause-specific death categories, censored counts, populations at risk by time and completeness of death data remain unverified. - Required materials and conditions: Death counts, timing, populations at risk, censoring and original tables - Materials to obtain first: Death counts, timing, populations at risk, censoring and original tables - Further research: Proposal: Original OS materials publishing death and follow-up data for the same allocated population - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What are the death events, participant denominators and original proportions" and link them to original locations. Cause-specific death categories, censored counts, populations at risk by time and completeness of death data remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What are the death events, participant denominators and original proportions. - Application exceptions: Do not add original death counts into new totals or risk differences or count participants without deaths as losses. - Remaining uncertainty: Cause-specific death categories, censored counts, populations at risk by time and completeness of death data remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C07, E04. - Related sources: R01 ### N25 · Does analysis of all 546 participants mean complete OS follow-up? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Inclusion of everyone in the full analysis population records the original analysis population. Distinguish 303/362 and 151/184 death counts from inclusion in analysis. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Specific survival, censoring, administrative closure and follow-up loss cannot be verified from the full-analysis description alone. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Specific survival, censoring, administrative closure and follow-up loss cannot be verified from the full-analysis description alone. - Required materials and conditions: OS analysis population, follow-up loss, censoring tables and sensitivity analyses - Materials to obtain first: OS analysis population, follow-up loss, censoring tables and sensitivity analyses - Further research: Proposal: Original tables from the same trial specifying differences between full analysis and actual follow-up information - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Does analysis of all 546 participants mean complete OS follow-up" and link them to original locations. Specific survival, censoring, administrative closure and follow-up loss cannot be verified from the full-analysis description alone. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Does analysis of all 546 participants mean complete OS follow-up. - Application exceptions: Do not subtract non-death participants or declare everyone missing or completely followed. - Remaining uncertainty: Specific survival, censoring, administrative closure and follow-up loss cannot be verified from the full-analysis description alone. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C07, E04. - Related sources: R01 ### N26 · What were the survival risk sets, censoring and time models? Verification status: Unverified Reading scope: Summary read; external materials not read - Current findings: Original values are median OS and the between-group HR. Actual risk sets by time, censoring and model information are not separately available in the preserved summary. - Why unverified: Direct details of this condition were not verified within the current preserved-summary and externally unread scope. Proportional-hazards assumptions, censoring rules, stratification or adjustment variables, time-dependent effects and post hoc sensitivity remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Proportional-hazards assumptions, censoring rules, stratification or adjustment variables, time-dependent effects and post hoc sensitivity remain unverified. - Required materials and conditions: Survival curves, risk-set tables, censoring rules, models and SAP - Materials to obtain first: Survival curves, risk-set tables, censoring rules, models and SAP - Further research: Proposal: Same-trial materials separately reporting original survival-analysis assumptions and sensitivity - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What were the survival risk sets, censoring and time models" and link them to original locations. Proportional-hazards assumptions, censoring rules, stratification or adjustment variables, time-dependent effects and post hoc sensitivity remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What were the survival risk sets, censoring and time models. - Application exceptions: Proportional-hazards assumptions, censoring rules, stratification or adjustment variables, time-dependent effects and post hoc sensitivity remain unverified. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Proportional-hazards assumptions, censoring rules, stratification or adjustment variables, time-dependent effects and post hoc sensitivity remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions E04, E05, C07. - Related sources: R01 ### N27 · Is non-significant OS being converted into zero effect or equivalence? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: HR 1.05 (95% CI 0.86~1.27), P=.68 records failure of the original improved-survival claim. The parent explicitly states that the confidence interval retained possible benefit. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Equivalence or noninferiority plans, justified equivalence margins and exclusion of every effect magnitude have not been verified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Equivalence or noninferiority plans, justified equivalence margins and exclusion of every effect magnitude have not been verified. - Required materials and conditions: Original intervals, test purpose, clinical importance and design limitations - Materials to obtain first: Original intervals, test purpose, clinical importance and design limitations - Further research: Proposal: Statistical materials clearly publishing original judgment criteria and interval interpretation - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Is non-significant OS being converted into zero effect or equivalence" and link them to original locations. Equivalence or noninferiority plans, justified equivalence margins and exclusion of every effect magnitude have not been verified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Is non-significant OS being converted into zero effect or equivalence. - Application exceptions: Null-result wording is not extended into exactly zero effect, equivalence or absence of harm. - Remaining uncertainty: Equivalence or noninferiority plans, justified equivalence margins and exclusion of every effect magnitude have not been verified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C08, E05. - Related sources: R01 ### N28 · What is the threshold for an OS difference important to patients? Verification status: Unverified Reading scope: Summary read; external materials not read - Current findings: Original materials present a hard overall-survival endpoint, HR and interval. A separate clinically important OS difference threshold is absent from this summary. - Why unverified: Direct details of this condition were not verified within the current preserved-summary and externally unread scope. Prespecified important differences, patient values, power and event-count assumptions remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Prespecified important differences, patient values, power and event-count assumptions remain unverified. - Required materials and conditions: Planned important difference, power or event-count assumptions and patient-outcome criteria - Materials to obtain first: Planned important difference, power or event-count assumptions and patient-outcome criteria - Further research: Proposal: Link justified importance criteria from the original plan with the relevant interval when supplied - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What is the threshold for an OS difference important to patients" and link them to original locations. Prespecified important differences, patient values, power and event-count assumptions remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What is the threshold for an OS difference important to patients. - Application exceptions: A sample of 546 or a hard endpoint does not by itself establish exclusion of every important effect. - Remaining uncertainty: Prespecified important differences, patient values, power and event-count assumptions remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions E05. - Related sources: R01 ### N29 · Is positive secondary disease control kept from being transferred into OS benefit? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Disease control was 56.1% versus 45.1% (P=.01); preserve the existing counterpoint's 11%p difference wording. This was a secondary result after failure of primary survival. - Why unverified: Some information for this item exists in the preserved summary and has been linked. DCR definitions, assessment times, denominators, CI, multiplicity and survival-prediction or mediation validation remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: DCR definitions, assessment times, denominators, CI, multiplicity and survival-prediction or mediation validation remain unverified. - Required materials and conditions: Original DCR tables, definitions, plans and boundaries from OS - Materials to obtain first: Original DCR tables, definitions, plans and boundaries from OS - Further research: Proposal: Reports linking DCR and OS within the same trial through their respective definitions, times and denominators - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Is positive secondary disease control kept from being transferred into OS benefit" and link them to original locations. DCR definitions, assessment times, denominators, CI, multiplicity and survival-prediction or mediation validation remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Is positive secondary disease control kept from being transferred into OS benefit. - Application exceptions: No new difference beyond the original 11%p is calculated, and positive DCR is not changed into positive OS. - Remaining uncertainty: DCR definitions, assessment times, denominators, CI, multiplicity and survival-prediction or mediation validation remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C08, E06, E09. - Related sources: R01 ### N30 · How does time to progression differ from OS? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Time to progression was a separate original result: 3.0 versus 2.6 months, HR 0.93 (95% CI 0.75~1.15). Its name is not interchanged with overall survival, DCR or progression-free survival. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Progression definitions, ascertainment, censoring or death handling, denominators, original P and analysis plans remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Progression definitions, ascertainment, censoring or death handling, denominators, original P and analysis plans remain unverified. - Required materials and conditions: TTP definitions, models, original results and distinction from OS - Materials to obtain first: TTP definitions, models, original results and distinction from OS - Further research: Proposal: Same-trial materials separately publishing progression or death analysis definitions and follow-up - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "How does time to progression differ from OS" and link them to original locations. Progression definitions, ascertainment, censoring or death handling, denominators, original P and analysis plans remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: How does time to progression differ from OS. - Application exceptions: Time to progression is not converted into PFS, survival benefit or a new duration difference. - Remaining uncertainty: Progression definitions, ascertainment, censoring or death handling, denominators, original P and analysis plans remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C06, C08, E09. - Related sources: R01 ### N31 · What was the original all-grade stomatitis comparison? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The original record reports all-grade stomatitis of 39.6% versus 4.9%. This is a safety outcome distinct from tumor control or survival. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Stomatitis event counts, safety denominators, collection or classification, times, CI and P remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Stomatitis event counts, safety denominators, collection or classification, times, CI and P remain unverified. - Required materials and conditions: Original stomatitis tables, safety population, grading criteria and duration - Materials to obtain first: Original stomatitis tables, safety population, grading criteria and duration - Further research: Proposal: Original safety materials linking stomatitis in the same exposed population with denominators and duration - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What was the original all-grade stomatitis comparison" and link them to original locations. Stomatitis event counts, safety denominators, collection or classification, times, CI and P remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What was the original all-grade stomatitis comparison. - Application exceptions: Stomatitis event counts, safety denominators, collection or classification, times, CI and P remain unverified. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Stomatitis event counts, safety denominators, collection or classification, times, CI and P remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions E10, H01, H03, H04. - Related sources: R01 ### N32 · What were the grade 3 or 4 anemia comparison and original statistical level? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Grade 3 or 4 anemia was 7.8% versus 3.3%, with the original safety comparison recorded as descriptive statistics. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Anemia event counts, denominators, baseline anemia, grading criteria, between-group CI or P and timing remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Anemia event counts, denominators, baseline anemia, grading criteria, between-group CI or P and timing remain unverified. - Required materials and conditions: Anemia safety tables, denominators or duration, classification and baseline status - Materials to obtain first: Anemia safety tables, denominators or duration, classification and baseline status - Further research: Proposal: Materials publishing hematologic harms from the same trial at the original population, timing and analysis level - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What were the grade 3 or 4 anemia comparison and original statistical level" and link them to original locations. Anemia event counts, denominators, baseline anemia, grading criteria, between-group CI or P and timing remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What were the grade 3 or 4 anemia comparison and original statistical level. - Application exceptions: Descriptive proportions are not newly calculated into significant risk increases, no-difference tests or incidence rates. - Remaining uncertainty: Anemia event counts, denominators, baseline anemia, grading criteria, between-group CI or P and timing remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions E10, H01, H03, H04. - Related sources: R01 ### N33 · What were the original grade 3 or 4 asthenia and decreased-appetite values? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Preserve grade 3 or 4 asthenia of 7.8% versus 5.5% and decreased appetite of 6.1% versus 0.5% separately. Original safety comparisons were descriptive statistics. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Event-specific denominators, participants versus event counts, co-occurring events, causes or timing, CI or P and classifications remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Event-specific denominators, participants versus event counts, co-occurring events, causes or timing, CI or P and classifications remain unverified. - Required materials and conditions: Original tables, denominators, grading, collection and timing for each safety event - Materials to obtain first: Original tables, denominators, grading, collection and timing for each safety event - Further research: Proposal: Safety materials reporting asthenia and decreased appetite as separate events under the same exposure - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What were the original grade 3 or 4 asthenia and decreased-appetite values" and link them to original locations. Event-specific denominators, participants versus event counts, co-occurring events, causes or timing, CI or P and classifications remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What were the original grade 3 or 4 asthenia and decreased-appetite values. - Application exceptions: Do not merge the two symptoms into a new composite event, participant total or risk difference. - Remaining uncertainty: Event-specific denominators, participants versus event counts, co-occurring events, causes or timing, CI or P and classifications remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions H01, H03, H04, E10. - Related sources: R01 ### N34 · How are asymptomatic hepatitis B reactivation and discontinuation distinguished? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The original record reports asymptomatic hepatitis B reactivation by central laboratory testing in 29 versus 10 participants, and discontinuation in 3 everolimus participants. Asymptomatic test results and medication discontinuation are separate events. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Reactivation criteria, baseline HBV or at-risk denominators, testing times, prophylaxis, discontinuation timing or attribution and CI or P remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Reactivation criteria, baseline HBV or at-risk denominators, testing times, prophylaxis, discontinuation timing or attribution and CI or P remain unverified. - Required materials and conditions: HBV testing criteria, populations at risk, group denominators or follow-up and original discontinuation tables - Materials to obtain first: HBV testing criteria, populations at risk, group denominators or follow-up and original discontinuation tables - Further research: Proposal: Safety materials linking HBV reactivation and discontinuation under the same exposure with populations at risk - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "How are asymptomatic hepatitis B reactivation and discontinuation distinguished" and link them to original locations. Reactivation criteria, baseline HBV or at-risk denominators, testing times, prophylaxis, discontinuation timing or attribution and CI or P remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: How are asymptomatic hepatitis B reactivation and discontinuation distinguished. - Application exceptions: Do not divide 29/10 or 3 discontinuations by full allocated denominators to calculate new proportions or risks. - Remaining uncertainty: Reactivation criteria, baseline HBV or at-risk denominators, testing times, prophylaxis, discontinuation timing or attribution and CI or P remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions H01, H02, H03, H04, H05. - Related sources: R01 ### N35 · What is the scope of safety denominators, exposure duration and complete collection? Verification status: Unverified Reading scope: Summary read; external materials not read - Current findings: The parent records stomatitis, hematologic or hepatic outcomes and Caution status. Distinguish the full randomized-analysis denominator from safety exposure or assessment denominators. - Why unverified: Direct details of this condition were not verified within the current preserved-summary and externally unread scope. Safety populations, actual exposure durations, event-specific populations at risk, collection or follow-up, post-discontinuation events, losses and rare harms remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Safety populations, actual exposure durations, event-specific populations at risk, collection or follow-up, post-discontinuation events, losses and rare harms remain unverified. - Required materials and conditions: Safety analysis definitions, exposure, all-event tables and collection or follow-up materials - Materials to obtain first: Safety analysis definitions, exposure, all-event tables and collection or follow-up materials - Further research: Proposal: Original reports from the same trial specifying safety populations, timing and missingness - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What is the scope of safety denominators, exposure duration and complete collection" and link them to original locations. Safety populations, actual exposure durations, event-specific populations at risk, collection or follow-up, post-discontinuation events, losses and rare harms remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What is the scope of safety denominators, exposure duration and complete collection. - Application exceptions: Safety populations, actual exposure durations, event-specific populations at risk, collection or follow-up, post-discontinuation events, losses and rare harms remain unverified. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Safety populations, actual exposure durations, event-specific populations at risk, collection or follow-up, post-discontinuation events, losses and rare harms remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions H02, H04, H06, H08. - Related sources: R01 ### N36 · What are baseline disease, concurrent treatment and alternative causes of harms? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Advanced hepatocellular carcinoma, Child-Pugh A, prior sorafenib failure or intolerance and supportive care are the original population or exposure context. Detailed medication attribution of recorded events is separate. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Baseline liver disease or HBV, anemia, concurrent medications, subsequent treatment, alternative causes and group-specific adjustment remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Baseline liver disease or HBV, anemia, concurrent medications, subsequent treatment, alternative causes and group-specific adjustment remain unverified. - Required materials and conditions: Baseline risks, concomitant or subsequent treatments, event attribution and original analyses - Materials to obtain first: Baseline risks, concomitant or subsequent treatments, event attribution and original analyses - Further research: Proposal: Supplementary safety materials separately publishing baseline disease and exposure or event relationships - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What are baseline disease, concurrent treatment and alternative causes of harms" and link them to original locations. Baseline liver disease or HBV, anemia, concurrent medications, subsequent treatment, alternative causes and group-specific adjustment remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What are baseline disease, concurrent treatment and alternative causes of harms. - Application exceptions: Do not newly assert that other causes were absent or all events were caused by everolimus. - Remaining uncertainty: Baseline liver disease or HBV, anemia, concurrent medications, subsequent treatment, alternative causes and group-specific adjustment remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions H05, E02, E10. - Related sources: R01 ### N37 · Who supplied research funding, study medication and placebo? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Preserve Novartis Pharmaceuticals sponsorship, study medication or placebo supply, data management, statistical analysis and writing support from original funding information and narrative. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Original contracts, funding details, complete individual-interest disclosures and current changes remain externally unread. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Original contracts, funding details, complete individual-interest disclosures and current changes remain externally unread. - Required materials and conditions: Original funding, product supply, contracts and disclosed interests - Materials to obtain first: Original funding, product supply, contracts and disclosed interests - Further research: Proposal: Original materials publishing actual-report funding, product supply and roles together - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Who supplied research funding, study medication and placebo" and link them to original locations. Original contracts, funding details, complete individual-interest disclosures and current changes remain externally unread. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Who supplied research funding, study medication and placebo. - Application exceptions: Original contracts, funding details, complete individual-interest disclosures and current changes remain externally unread. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Original contracts, funding details, complete individual-interest disclosures and current changes remain externally unread. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C10. - Related sources: R01 ### N38 · How did the sponsor participate in design, data collection and analysis? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The existing research description records Novartis participation in design, collection through its data-management system and analysis by its statistical team. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Specific scope of full data access, original statistical responsibility, independent reanalysis and operational contracts remains unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Specific scope of full data access, original statistical responsibility, independent reanalysis and operational contracts remains unverified. - Required materials and conditions: Design, collection and analysis role declarations, data access and statistical responsibility - Materials to obtain first: Design, collection and analysis role declarations, data access and statistical responsibility - Further research: Proposal: Original declarations or supplementary materials specifying reported roles and the scope of actual analysis disclosure - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "How did the sponsor participate in design, data collection and analysis" and link them to original locations. Specific scope of full data access, original statistical responsibility, independent reanalysis and operational contracts remains unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: How did the sponsor participate in design, data collection and analysis. - Application exceptions: Sponsor involvement alone does not justify deleting original numbers or deriving a new null effect or bias magnitude. - Remaining uncertainty: Specific scope of full data access, original statistical responsibility, independent reanalysis and operational contracts remains unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C10, E04. - Related sources: R01 ### N39 · What were employee-author, writing and submission-decision roles? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The preserved summary records employee authors participating in interpretation, writing and submission decisions, and Novartis paying ApotheCom's medical-writing costs. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Complete individual-author COI, writing or approval and submission-authority contracts and role changes remain unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Complete individual-author COI, writing or approval and submission-authority contracts and role changes remain unverified. - Required materials and conditions: Author employment or COI, contributions, writing and publication-role declarations - Materials to obtain first: Author employment or COI, contributions, writing and publication-role declarations - Further research: Proposal: Materials linking original author or sponsor roles and disclosed interests - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What were employee-author, writing and submission-decision roles" and link them to original locations. Complete individual-author COI, writing or approval and submission-authority contracts and role changes remain unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What were employee-author, writing and submission-decision roles. - Application exceptions: Complete individual-author COI, writing or approval and submission-authority contracts and role changes remain unverified. Preserve both relevant summary information and unverified matters; empty values are not filled with new numbers or verdicts. - Remaining uncertainty: Complete individual-author COI, writing or approval and submission-authority contracts and role changes remain unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C10. - Related sources: R01 ### N40 · What is the actual scope of independent replication or separate safety materials? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: The preserved evidence or citation list contains 1 EVOLVE-1 report record; parent replication R1 and independence I0 are historical axes. The two sheets or repeated safety citations are not counted as separate replications. - Why unverified: Some information for this item exists in the preserved summary and has been linked. No new search was conducted for independent trials, additional report or cohort lists, duplicate events or external safety or regulatory materials. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: No new search was conducted for independent trials, additional report or cohort lists, duplicate events or external safety or regulatory materials. - Required materials and conditions: Reports, study families, COI, shared outcomes and contrary-material lists - Materials to obtain first: Reports, study families, COI, shared outcomes and contrary-material lists - Further research: Proposal: Relationship records specifying repeated citation, shared populations or separate populations when separate materials are actually supplied - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "What is the actual scope of independent replication or separate safety materials" and link them to original locations. No new search was conducted for independent trials, additional report or cohort lists, duplicate events or external safety or regulatory materials. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: What is the actual scope of independent replication or separate safety materials. - Application exceptions: One literature record or two existing sheets are not converted into current worldwide trial totals or confirmed independent replication. - Remaining uncertainty: No new search was conducted for independent trials, additional report or cohort lists, duplicate events or external safety or regulatory materials. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C02, C10, E07, H07. - Related sources: R01 ### N41 · At what level are efficacy outcomes and descriptive harms described? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Retain null OS, positive secondary DCR and descriptive harms as their respective original results. Parent safety Caution is historical and does not confirm safety or absence of all harms. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Current synthesis of event-specific comparative estimates, causal attribution and long-term or rare harms remains unverified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Current synthesis of event-specific comparative estimates, causal attribution and long-term or rare harms remains unverified. - Required materials and conditions: Original efficacy and safety tables, definitions, denominators or times and interpretive scope - Materials to obtain first: Original efficacy and safety tables, definitions, denominators or times and interpretive scope - Further research: Proposal: Original reports separately specifying the different analysis levels for efficacy and harms - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "At what level are efficacy outcomes and descriptive harms described" and link them to original locations. Current synthesis of event-specific comparative estimates, causal attribution and long-term or rare harms remains unverified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: At what level are efficacy outcomes and descriptive harms described. - Application exceptions: Non-significant survival or positive DCR does not erase harms, and descriptive statistics alone do not create a new causal safety verdict. - Remaining uncertainty: Current synthesis of event-specific comparative estimates, causal attribution and long-term or rare harms remains unverified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions E10, H09, C08. - Related sources: R01 ### N42 · How are parent grade, score, false or empty axis values and Korean or English drafts preserved? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Preserve parent D, 34, Caution and axes B/H/R1/I0/E0/B0/C0; coprimary split false, large hard-endpoint RCT true, no-human-study false, primary-failed-secondary-positive true and empty override reasons. Complete Korean and English drafts and historical synthesis or grade decisions are context. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Original cross-checking, grades and axes were not automatically applied as current review completion or selected subclaim values. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Original cross-checking, grades and axes were not automatically applied as current review completion or selected subclaim values. - Required materials and conditions: Separate copies preserving subclaim and parent values, Korean or English drafts, axes and historical verdict - Materials to obtain first: Separate copies preserving subclaim and parent values, Korean or English drafts, axes and historical verdict - Further research: Proposal: Preserved records separating complete pre-change originals, events, versions and decisions when verdict corrections are actually supplied - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "How are parent grade, score, false or empty axis values and Korean or English drafts preserved" and link them to original locations. Original cross-checking, grades and axes were not automatically applied as current review completion or selected subclaim values. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: How are parent grade, score, false or empty axis values and Korean or English drafts preserved. - Application exceptions: The parent's 34 points, B0/C0 or cross-check-applied history are not inherited as subclaim scores or axes, new fulfillment or review completion. - Remaining uncertainty: Original cross-checking, grades and axes were not automatically applied as current review completion or selected subclaim values. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C01, C09, E06. - Related sources: R01 ### N43 · Do the cutoff date, corrections and empty values differ from current production dates? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: Preserve original cutoff 2026-08-26 and empty correction and deliberation values. Bibliography or registration-agreement descriptions in the original Korean and English drafts are historical, while the current writing time is a production event. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Original additional-cutoff and detailed-classification fields are absent; no new search, registration, correction or retraction comparison or external reading was performed. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Original additional-cutoff and detailed-classification fields are absent; no new search, registration, correction or retraction comparison or external reading was performed. - Required materials and conditions: Distinguishing original cutoff, correction, retraction or search history from production events - Materials to obtain first: Distinguishing original cutoff, correction, retraction or search history from production events - Further research: Proposal: Update records distinguishing historical scope from current additional events when materials or corrections are actually supplied - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Do the cutoff date, corrections and empty values differ from current production dates" and link them to original locations. Original additional-cutoff and detailed-classification fields are absent; no new search, registration, correction or retraction comparison or external reading was performed. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Do the cutoff date, corrections and empty values differ from current production dates. - Application exceptions: Empty corrections are not certified as no current corrections, and the original verification date is not changed into the current review date. - Remaining uncertainty: Original additional-cutoff and detailed-classification fields are absent; no new search, registration, correction or retraction comparison or external reading was performed. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C09, C03. - Related sources: R01 ### N44 · Is the scope kept from extending to current applicability, products or treatment decisions? Verification status: Partly verified Reading scope: Summary read; external materials not read - Current findings: This sheet documents the specified existing claim and EVOLVE-1's historical comparison, outcomes and gaps. Other products or doses, current treatment lines and individual treatment choice are outside this production scope. - Why unverified: Some information for this item exists in the preserved summary and has been linked. Current clinical practice, product or regulatory status, individual suitability and direct superiority of other treatments were not verified. Existing content review remains incomplete; this does not establish clinical-condition fulfillment, zero effect or absence of materials. - Reason for missing information: Current clinical practice, product or regulatory status, individual suitability and direct superiority of other treatments were not verified. - Required materials and conditions: Appropriate direct materials for extended questions and applicability differences from the original trial - Materials to obtain first: Appropriate direct materials for extended questions and applicability differences from the original trial - Further research: Proposal: Research-gap updates distinguishing selected scope, outcomes and harms when additional materials are authorized and supplied - Conditions for verification: Distinguish preserved values, direct scope and unverified matters relevant to "Is the scope kept from extending to current applicability, products or treatment decisions" and link them to original locations. Current clinical practice, product or regulatory status, individual suitability and direct superiority of other treatments were not verified. - Why this condition is needed: This condition is needed to separately document the selected improved-overall-survival question: Is the scope kept from extending to current applicability, products or treatment decisions. - Application exceptions: No new medication or dosing instructions, substitution or discontinuation of sorafenib or other treatments, or anticancer-treatment choices are created. - Remaining uncertainty: Current clinical practice, product or regulatory status, individual suitability and direct superiority of other treatments were not verified. - Referenced methods: Own question-specific conditions informed by the preserved summary's original locations and family definitions C09, E08, E09, H08, H09. - Related sources: R01 ## Evidence and sources ### R01 Zhu AX, Kudo M, Assenat E, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014;312:57-67. PMID: 25058218. [PubMed](https://pubmed.ncbi.nlm.nih.gov/25058218/) Materials actually read: Summary read; external abstracts, full texts and registrations unread Findings recorded in the summary: Preserve OS HR 1.05 (95% CI 0.86~1.27), P=.68. The original subclaim note and parent describe a null result for improved overall survival. Record level: Not recorded Independent replication: The overall-survival and disease-control sheets share the same EVOLVE-1, PMID25058218, NCT01035229 and 546 participants (362/184). OS, DCR, TTP and safety are separated as outcome units; no additional trials or new participants are added. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Stored summary | Preserved complete summary copy | Preserved summary copy acquired; summary read | Summary read | Parent Korean and English drafts, two existing questions, bibliography, registration and original values were read for production; this is not reading clinical original materials. | | External abstract | External material unread; no access attempts | Access not attempted; not obtained | Not read | The original PubMed bibliographic URL was linked. Abstract reading, material acquisition and operation tests were not performed. | | External full text | External material unread; no access attempts | Access not attempted; not obtained | Not read | The original bibliographic URL links identity; it does not certify a direct full-text acquisition or reading URL. | | External registration | External material unread; no access attempts | Access not attempted; not obtained | Not read | Preserve the registration-ID record and original agreement wording. No registration URL absent from the existing summary was constructed, and current registration was not read. | | Required protocol | Not acquired; detailed existence unverified | Access not attempted; not obtained | Not read | Original details of OS definitions, DCR or progression criteria, assessment times, exposure and blinding are required. Lack of acquisition is not converted into confirmed non-registration or selective reporting. | | Required analysis plan | Not acquired; detailed existence unverified | Access not attempted; not obtained | Not read | Original OS HR analysis, DCR intervals or tests, hierarchy, multiplicity and missing-data handling materials are required. No new CI or verdict is created. | | Required result tables and safety material | Not acquired; detailed existence unverified | Access not attempted; not obtained | Not read | Original tables are required to distinguish allocation or full analysis from DCR assessment, OS censoring, safety or at-risk denominators and descriptive harms. | | Required sponsorship and competing-interest materials | Not acquired; detailed existence unverified | Access not attempted; not obtained | Not read | Original sponsorship, design, collection, analysis, writing and submission-role descriptions are preserved; complete COI, contracts and original declarations remain unread. | ## Review criteria and methods These are Chamgap's own application conditions, informed by the relevant sections of official methodological guidance. They do not constitute official assessment-tool certification or a new efficacy score. - M03 [Cochrane Handbook 6.5 (2024), chapter updated 2023-08](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-03) · §3.1, §3.2.1–3.2.3, MECIR C5/C7/C13 · Clearly record the question, eligibility conditions and reasons for changes, and distinguish variations in interventions. · Methodological principles stated in existing pilot materials and condition templates were referenced. The methodological text was not reviewed again in this work. - M04 [Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-04) · §4.5, §4.6.1–4.6.3, MECIR C42 · Distinguish studies from reports and link them; do not omit a study solely because results are unreported. · Methodological principles stated in existing pilot materials and condition templates were referenced. The methodological text was not reviewed again in this work. - M08 [Cochrane Handbook 6.5 (2024), chapter updated 2019-10](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-08) · §8.1–8.2.3, Table 8.2.a · Define the outcome and effect of interest, then examine randomization, deviations, missing data, measurement and selective reporting. · Methodological principles stated in existing pilot materials and condition templates were referenced. The methodological text was not reviewed again in this work. - M15 [Cochrane Handbook 6.5 (2024), chapter updated 2023-08](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-15) · §15.2.4, §15.3.1–15.3.3 · Distinguish effect estimates, intervals, importance and applicability. Sample size alone does not determine precision. · Methodological principles stated in existing pilot materials and condition templates were referenced. The methodological text was not reviewed again in this work. - M19 [Cochrane Handbook 6.5 (2024), chapter updated 2019-10](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-19) · §19.1.2, §19.2.1–19.2.4 · Harm questions may require different designs, populations and follow-up from efficacy questions. Case reports do not establish incidence rates. · Methodological principles stated in existing pilot materials and condition templates were referenced. The methodological text was not reviewed again in this work. ## What the statuses mean - Met: The original content has been reviewed as meeting the conditions. This status is not used in this preparation. - Partly verified: Some information in the stored summary was linked during preparation; clinical verification or review is not complete. - Unverified: Required direct values, definitions or materials have not been established within the current storage and reading scope. This does not mean zero effect, no papers or failed access. - Review incomplete: Review of existing content or actual review incomplete. - Not reported: Used only when original materials were actually read and the outcome was judged unreported. Not used for external materials unread in this work. - Inaccessible: Used only when an actual access attempt has a recorded failure. Not used for access that was not attempted in this work. - Insufficient evidence for the conditions: Indicates insufficient direct materials for the relevant scope or conditions; it is not a new grade. - Not applicable: Used when the reason it does not apply to the original question is stated. - Conflicting data: Retains the scope of conflicting statements in original materials; it is not an arbitrary reassessment. ## Change history 2026-10-11 · Public page/materials 1.0. A public view and materials were prepared from the existing 44 items. No new clinical search, verification-status change or scoring was performed.