ESA anemia correction × locoregional tumor control during head-and-neck radiotherapy — evidence checklist

Required evidence, verification status and materials actually read
Item	AVerification status	BReading scope	CReview item	DCurrent findings	EWhy unverified	FRequired materials and conditions	GFurther research
1	Partly verified	Full text not readStored summary read	N01 · Evidence conditionIs the selected original question improved locoregional tumor control?Required	The selected existing question is improved locoregional tumor control. The parent describes harm from ESA anemia correction during head-and-neck radiotherapy. The question's improvement direction is distinguished from the observed worsening. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. The final count of independent claims remains undetermined.	Link selected and parent claims, disease, exposure and failure direction	Proposal: If the question actually changes, separately record its original wording and excluded scope.
2	Partly verified	Full text not readStored summary read	N02 · Evidence conditionAre the subclaim's grade F and note separate from parent F12 and axes?Required	Selected grade F and the note that five-year failure worsened to 47% versus 34% are preserved. Subclaim score, status and axes are absent and not recorded. Parent F12, safety Warning and axes belong to the parent. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. The original materials contain no distinct subclaim score, status or axes.	Locations of actual and absent subclaim fields and original parent values	Proposal: If subclaim fields are actually added, distinguish the original version from the new event.
3	Partly verified	Full text not readStored summary read	N03 · Evidence conditionDo repeated refutation, design limitations and cross-checking constitute current review?Required	The original parent describes F12 based on repeated refutation across three ESA trials, DAHANCA harm, early stopping at a planned interim analysis and open-label design. RX, cross-checking, true/false indications and empty values are historical records. R01 R02 R03 R04	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. No current RoB2/GRADE assessment, clinical reassessment or methodological certification was performed.	Korean and English wording, axes, verdict, corrections and methodological statements	Proposal: If new evidence is requested, separate the original version from the new update event.
4	Partly verified	Full text not readStored summary read	N04 · Evidence conditionWhich materials were actually read, and which external materials remain unread?Required	The selection and complete preserved summary were read for production. External abstracts, full texts, registrations, plans, original FDA warnings and verdict 2925's page and links remain unread; access was not attempted. R01 R02 R03 R04	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. No search of current external contents, all recent literature or regulatory materials was performed.	Acquisition and reading scope for preserved summaries and each external material	Proposal: If material and reading records are supplied, record only the actual level.
5	Partly verified	Full text not readStored summary read	N05 · Evidence conditionHow are trials, the review and initial and follow-up reports linked?Required	DAHANCA 10, ENHANCE, the same-trial initial and long-term RTOG 99-03 report group and the five-RCT review are distinguished. The reference to 2925 concerns another indication and is not a report of this cancer trial. R01 R02 R03 R04	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Unique trial and participant totals and review inclusion and overlap were not directly verified.	Original bibliography, review inclusion, initial and long-term reports and participant relationships	Proposal: If original lists are supplied, link each report to the same, different or uncertain study family.
6	Partly verified	Full text not readStored summary read	N06 · Evidence conditionWhat were DAHANCA's population and Hb eligibility conditions?Required	The setting is head-and-neck squamous-cell carcinoma radiotherapy. The original DAHANCA condition included patients with Hb below 14.0 g/dL. Detailed stage, exact age and site and baseline anemia cause are absent from the summary. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Detailed stage, site, age, anemia cause and baseline risk remain unverified.	Stage, site, inclusion and exclusion, Hb, anemia cause and baseline risk	Proposal: If original population tables are supplied, distinguish the actual population from gaps for other cancers and goals.
7	Partly verified	Full text not readStored summary read	N07 · Evidence conditionWhat were darbepoetin exposure, goals and hematologic response in the trial?Required	The historical DAHANCA condition used weekly darbepoetin during radiotherapy. Exact dose, formulation, route, Hb target and stopping rules are absent from the summary. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Dose, route, actual adherence, achieved Hb and discontinuation details remain unverified.	Nominal and actual drug exposure, Hb target, changes and discontinuation	Proposal: If original exposure records are supplied, record trial conditions and actual use and goals.
8	Partly verified	Full text not readStored summary read	N08 · Evidence conditionWhat were control radiotherapy and shared or concurrent cancer treatments?Required	The original comparison is radiotherapy with an ESA added versus control. The review describes radiotherapy plus EPO versus radiotherapy alone. Specific radiotherapy and other concomitant treatments in each trial are absent from the summary. R01 R02 R03 R04	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Concomitant treatment, radiotherapy conditions and their balance remain unverified for each trial.	Trial-specific controls, radiotherapy plans and shared or concomitant cancer and anemia treatment	Proposal: If original comparison materials are supplied, distinguish the added drug from shared and other treatments.
9	Partly verified	Full text not readStored summary read	N09 · Evidence conditionAre planned 600, randomized 522 and evaluable 513 different stages?Required	DAHANCA's planned 600, 522 randomized at stopping and 513 evaluable (254/259) are separately preserved. Planning, allocation and evaluation represent different denominators. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Reasons for differences between allocation and evaluation, original arm correspondence and endpoint-denominator details remain externally unread.	Allocation and evaluation flow by arm, correspondence of 254/259 to arms, exclusions and missingness	Proposal: If original flow diagrams are supplied, record stages and inclusion rules by arm.
10	Partly verified	Full text not readStored summary read	N10 · Evidence conditionWhat are the locoregional-failure time, five-year values and HR?Required	The primary endpoint was time to locoregional failure. Original worsening results were five-year cumulative failure of 47% with darbepoetin versus 34% in controls, HR 1.53 (95% CI 1.16–2.02). R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Failure components and definition, population at risk, censoring and model remain unverified.	Failure definition, timepoint and time, denominator, HR model and interval	Proposal: If original results and methods are supplied, link cumulative values to the time-to-event estimate.
11	Partly verified	Full text not readStored summary read	N11 · Evidence conditionHow should lower-is-better failure and the improvement question be read?Required	The original reader answer explicitly states that lower locoregional failure is better. Failure of 47% versus 34% is originally described as worsening, rather than improvement. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Detailed endpoint-specific success and failure adjudication rules remain unverified.	Endpoint direction and relationship between question and result	Proposal: If original definitions are added, record actual directions and interpretations of other endpoints.
12	Partly verified	Full text not readStored summary read	N12 · Evidence conditionAre the five-year cumulative proportion and time-to-failure HR the same measure?Required	Five-year cumulative locoregional failure and the time-to-failure HR are separate expressions. The original HR is not converted into a simple five-year risk ratio or difference in cumulative percentages. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Cumulative estimation, proportional hazards, competing risks and adjustment remain unverified.	Cumulative estimation, censoring, HR estimand, time and competing events	Proposal: If original statistical methods are supplied, distinguish definitions of cumulative estimation and hazard comparisons.
13	Unverified	Full text not readStored summary read	N13 · Evidence conditionWhat are the actual analysis and risk denominators for locoregional outcomes?Required	The original evaluable 513 (254/259) and five-year failure percentages are preserved. The five-year population at risk, follow-up, censoring and actual analysis denominators for each endpoint are absent from the summary. R01	Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Five-year risk population, event counts and endpoint-specific analyses and censoring remain unverified.	Endpoint-specific analysis and risk populations, events and people, censoring and missingness	Proposal: If original risk tables or flow diagrams are supplied, distinguish evaluation from timepoint and endpoint denominators.
14	Partly verified	Full text not readStored summary read	N14 · Evidence conditionWhat was the actual scope of open-label design and central blinded review?Required	The original DAHANCA account describes open-label design and says locoregional failure was not uniformly adjudicated through central blinded imaging review for every patient. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Patient-specific adjudication pathways, partial central review and assessor and analyst roles remain unverified.	Failure diagnosis and adjudication, imaging and clinical pathways and blinding by role	Proposal: If original adjudication methods are supplied, record actual pathways and limitations by role.
15	Unverified	Full text not readStored summary read	N15 · Evidence conditionWhat is known about randomization, allocation concealment and baseline balance?Required	The original summary describes DAHANCA as a multicenter randomized phase 3 trial. Actual tables or methods for sequence generation, concealment, stratification, baseline and cancer-treatment balance are absent. R01	Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Direct methods for allocation, concealment and baseline balance remain unverified.	Allocation procedures, concealment, baseline and stratification factors and treatment balance	Proposal: If original methods and baseline data are supplied, distinguish design labels from actual procedures.
16	Partly verified	Full text not readStored summary read	N16 · Evidence conditionWhat does early stopping at the planned interim analysis preserve?Required	The original trial account states that inferiority of the experimental arm at a planned interim analysis led to stopping at 522, before the planned 600. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Interim thresholds, boundaries, multiplicity, committee and subsequent follow-up details remain unverified.	Interim timing and thresholds, committee, alpha, stopping and subsequent follow-up	Proposal: If original plans and stopping records are supplied, record prior rules and actual stopping and follow-up.
17	Partly verified	Full text not readStored summary read	N17 · Evidence conditionDoes hematologic correction constitute a tumor-control benefit?Required	The original crux states that anemia measures improved but cancer control and survival worsened. Actual Hb changes, responders and target attainment are absent from the summary. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Quantitative Hb response, tumor oxygenation and mediation analyses remain unverified.	Hematologic response, achieved Hb, denominator, tumor oxygenation and direct events	Proposal: If original response data are supplied, record Hb measures and clinical outcomes separately.
18	Partly verified	Full text not readStored summary read	N18 · Evidence conditionWhat is the original event-free-survival value?Supplementary	DAHANCA event-free survival HR 1.36 (1.09–1.69) is described in the original harmful direction. This is a different outcome from the locoregional-failure HR. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. EFS components, model, denominator and detailed interval confidence level remain unverified.	EFS definition and components, denominator, HR model and interval confidence level	Proposal: If original results and methods are supplied, link EFS components and estimand to that value.
19	Partly verified	Full text not readStored summary read	N19 · Evidence conditionWhat is the disease-specific-death result?Supplementary	DAHANCA disease-specific-death HR 1.43 (1.08–1.90) points in the original harmful direction. It is separate from overall death and failure. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Cause-of-death adjudication, events, risk population and detailed interval confidence level remain unverified.	Cause-of-death adjudication, events and time, denominator, model and interval	Proposal: If original mortality outcomes are supplied, record causes, denominators and estimates separately.
20	Partly verified	Full text not readStored summary read	N20 · Evidence conditionWhat is the original overall-death HR?Supplementary	DAHANCA overall-death HR 1.30 (1.02–1.64) is described in the original harmful direction. It is not mixed with numbers from other survival or failure outcomes. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Original overall-death count, risk population and detailed interval confidence level remain unverified.	Overall death, risk population and denominator, time, model and interval	Proposal: If original mortality tables are supplied, record the actual overall-death estimate, time and denominator.
21	Partly verified	Full text not readStored summary read	N21 · Evidence conditionIs the sibling survival-improvement question separate from the main tumor question?Supplementary	The sibling survival question is improved survival, grade F, with a note about harmful disease-specific and overall death. It is preserved as context and remains separate from the selected locoregional question. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. This record also contains no distinct score, status or axes for the sibling.	Existing sibling question, endpoint definitions and denominators and original-result links	Proposal: If the original question changes, separately record each existing question and its links.
22	Unverified	Full text not readStored summary read	N22 · Evidence conditionWhat are the details of follow-up, treatment deviations, missingness and censoring?Required	Evaluable 513, five-year cumulative results and early stopping are preserved. Individual follow-up, treatment deviation or crossover, exclusions, censoring and ITT/PP details are absent from the summary. R01	Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Individual follow-up and deviations, ITT/PP and censoring and missing-data handling details remain unverified.	Endpoint-specific flow, follow-up and censoring, treatment deviations and missing-data handling	Proposal: If original flow and analyses are supplied, distinguish allocation, evaluation, risk populations and losses.
23	Partly verified	Full text not readStored summary read	N23 · Evidence conditionWhat history underlies the original registration-absence statements?Required	The original DAHANCA and ENHANCE registration values say absent because they predate registration requirements; RTOG records NCT00004917, and the review says not applicable. These original expressions are preserved; external registration existence was not currently verified. R01 R02 R03 R04	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. External registration existence and prior plans remain unread.	Original registration, timing, contemporaneous records and plans and changes	Proposal: If original registration and planning materials are supplied, distinguish actual existence and contents from original history.
24	Partly verified	Full text not readStored summary read	N24 · Evidence conditionWere prior endpoints, interim plans and the hierarchy of multiple outcomes read?Required	The original account includes primary failure, a planned interim analysis and major survival outcomes. Protocols, SAPs, all secondary and exploratory hierarchies, multiplicity and changes remain unread. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Direct documents for prior hierarchies, testing and changes remain unverified.	Original plans, prior hierarchy, interim and final testing and changes	Proposal: If original plans are supplied, distinguish contemporaneous roles from reports and follow-up.
25	Unverified	Full text not readStored summary read	N25 · Evidence conditionWhat are the clinical thresholds, individual effects and subgroups?Supplementary	Original failure and HR intervals and harmful-survival statements are available. Clinical-success thresholds, individual-response criteria and Hb, stage or population interactions are absent from the summary. R01	Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Prior clinical thresholds and direct subgroup effects and denominators remain unverified.	Prior importance thresholds and subgroup hypotheses, interactions, denominators and intervals	Proposal: If original plans or subgroup data are supplied, distinguish overall estimates from separate conditions.
26	Partly verified	Full text not readStored summary read	N26 · Evidence conditionWhat are ENHANCE's original population, design and RR results?Supplementary	The original ENHANCE notation is 351 patients (epoetin beta 180, placebo 171), ITT. Primary locoregional progression-free survival adjusted RR 1.62 (95% CI 1.22–2.14), P=.0008, and survival RR 1.39 (1.05–1.84) point in the original harmful direction. R02	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Adjustment variables, actual endpoints and ITT handling and detailed survival-interval confidence level remain unverified.	PFS and survival definitions, adjusted model, actual denominators, ITT and intervals	Proposal: If original ENHANCE methods and tables are supplied, record RR notation, estimand and endpoint-specific analyses.
27	Partly verified	Full text not readStored summary read	N27 · Evidence conditionHow do epoetin beta, epoetin alfa and darbepoetin exposures differ?Supplementary	The original verdict concerns three ESAs in the same head-and-neck radiotherapy setting, rather than one drug alone. Trial-specific doses, Hb targets, actual exposures and combinations are not detailed in the summary. R01 R02 R03	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Direct details of trial-specific targets, exposures, combinations and actual Hb remain unverified.	Drug-specific formulation, amount and targets, shared and different treatments and populations	Proposal: If original intervention data are supplied, record drugs, targets and trial-specific conditions separately.
28	Partly verified	Full text not readStored summary read	N28 · Evidence conditionWhat are RTOG's initial and long-term endpoint values?Supplementary	RTOG's 148 patients are described as showing no epoetin alfa benefit. Three-year failure 44% versus 36% (P=.56), five-year failure 46.2% versus 39.4% (P=.42) and OS 36.9% versus 38.2% (P=.54) are separately preserved. R03	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Actual analysis denominators, original CIs and models and detailed OS timepoint definitions remain unverified.	Timepoint-specific failure and OS, denominators, estimates, CIs and analysis plans	Proposal: If original RTOG tables are supplied, link each timepoint and endpoint to its original intervals and denominators.
29	Partly verified	Full text not readStored summary read	N29 · Evidence conditionDo the two RTOG PMIDs refer to reports of the same trial?Supplementary	The RTOG citation preserves initial PMID 17716826 and long-term PMID 25670542 together. Its original flag groups reports of the same trial as one. The URL identifies the long-term report's bibliography. R03	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Actual follow-up and denominators of the follow-up report and each original full text remain unread.	Initial and follow-up populations, timepoints and analysis and report relationships	Proposal: If original reports are supplied, distinguish same-cohort follow-up from separate trials.
30	Partly verified	Full text not readStored summary read	N30 · Evidence conditionCan the five-RCT, 1,397-participant review be added to original trials?Supplementary	The original review size is five RCTs and 1,397 participants. Report and included-trial lists and overlap with current original trials and follow-up were not directly read. R04	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Review inclusion, contributions and unique trial and participant totals remain undetermined.	Inclusion and contribution lists, trial identities, populations and timepoints and overlap	Proposal: If original inclusion tables are supplied, link the review to unique original study families.
31	Partly verified	Full text not readStored summary read	N31 · Evidence conditionWhat is the event direction of the review's ORs?Supplementary	OS Peto OR 0.73 (95% CI 0.58–0.91) and locoregional PFS OR 0.63 (0.49–0.80) are originally described as worse with radiotherapy plus EPO and favoring radiotherapy alone. R04	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. OR coding, synthesis model and detailed PFS-interval confidence level remain unverified.	Review event and success coding, models and endpoint-specific contributions and intervals	Proposal: If original review tables are supplied, record OR coding, estimands and contributions.
32	Unverified	Full text not readStored summary read	N32 · Evidence conditionWhat are the review's timing, subsets, heterogeneity and direct comparisons?Supplementary	The review's original bibliography is from 2009, whereas the original DAHANCA report is from 2018. Actual inclusion and updates, contributions by drug, target and timepoint, heterogeneity and subgroup analyses are absent from the summary. R04	Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Temporal relationships between versions and inclusion, subsets and quantitative heterogeneity remain unverified.	Review version, inclusion timing, endpoint subsets, synthesis, heterogeneity and conditions	Proposal: If original review tables are supplied, record versions and actual included families and conditions.
33	Partly verified	Full text not readStored summary read	N33 · Evidence conditionAre repeated refutation in the same indication and other goals distinguished?Supplementary	The original scope is limited to improved tumor control during cancer radiotherapy. Kidney-disease anemia and transfusion reduction in very-low-birth-weight preterm infants, verdict 2925 B72, concern different populations and goals. R01 R02 R03 R04	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Pages and original materials for other indications remain unread.	Direct questions, exposures and endpoints for each indication and goal	Proposal: If materials for another requested question are supplied, record its original unit and population separately.
34	Partly verified	Full text not readStored summary read	N34 · Harm informationWhat is the original statement of no differences in ancillary safety?Supplementary	The original counterview says no excess serious adverse events, cardiovascular increase or differences in acute or late radiation toxicity were identified. Quantitative events, denominators, CIs and P values are absent from the summary. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Direct safety event counts, intervals and collection methods remain unverified.	Safety definitions and collection, individual events and denominators, estimates and intervals	Proposal: If original safety tables are supplied, record original observations and intervals for each item.
35	Partly verified	Full text not readStored summary read	N35 · Harm informationAre major tumor and survival harms separate from safety collection?Supplementary	The original explanation states that demonstrated harm came from primary and major tumor-control and survival endpoints, rather than ancillary safety items. A complete list of all adverse events is absent from the summary. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Complete harm definitions, collection, discontinuation and severity tables remain unverified.	Clinical-harm and safety endpoints, collection and adjudication, severity and discontinuation	Proposal: If original safety and endpoint data are supplied, distinguish actual clinical outcomes from separate collection.
36	Unverified	Full text not readStored summary read	N36 · Harm informationWhat are harm-event, participant and time denominators and timepoints?Supplementary	Original context includes evaluable 513, five-year tumor outcomes and interim stopping. Numbers and time at risk for each safety event, onset, recovery, exposure and discontinuation timing are absent. R01	Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Denominators, time, discontinuation and recovery for each safety event remain unverified.	Safety-specific denominators and durations, event timing and treatment and follow-up discontinuation	Proposal: If original safety flow is supplied, record efficacy evaluation separately from safety exposure and time.
37	Unverified	Full text not readStored summary read	N37 · Harm informationWhat is known about baseline cancer risk, concurrent treatments and alternative attribution?Supplementary	Radiotherapy and ESA comparisons and clinical worsening are original-summary observations. Actual event-specific details of baseline and concurrent treatments, disease characteristics, other exposures and adjustment are absent. R01	Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Individual-event alternatives, mechanisms, concurrent treatments and adjustment details remain unverified.	Baseline and concurrent exposures, event attribution, adjustment and alternative explanations	Proposal: If original methods and event data are supplied, distinguish randomized comparisons from individual causes and mechanisms.
38	Unverified	Full text not readStored summary read	N38 · Harm informationWhat is known about missing and complete safety and clinical follow-up?Supplementary	Original history includes evaluation and allocation, early stopping and open-label design. Safety surveillance, follow-up losses, omissions, censoring and completeness of all event reporting are absent from the summary. R01	Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Safety follow-up, omissions and overall reporting completeness remain unverified.	Safety and clinical flow, losses and omissions, reporting and censoring and sensitivity	Proposal: If original flow and surveillance records are supplied, distinguish observed outcomes from uncaptured and missing data.
39	Partly verified	Full text not readStored summary read	N39 · Harm informationWhat is the scope of FDA warnings, original harm, current verification and causality?Supplementary	Original advertising interpretation and safety explanation preserve the FDA boxed warning about shortened cancer survival and tumor progression or recurrence. The preserved summary contains no regulatory-original URL or separate citation. Current approvals and warning contents were not queried. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Official warning and approval texts, latest versions and direct mechanistic verification remain unread.	Original regulatory text and versions, indications and clinical-outcome and judgment scope	Proposal: If original regulatory materials are supplied, distinguish historical statements from direct contents and current updates.
40	Partly verified	Full text not readStored summary read	N40 · Harm informationDoes this answer questions about other cancers, Hb targets, populations or long-term and rare harms?Supplementary	The original verdict concerns tumor control during head-and-neck radiotherapy. Direct results for other cancers, populations, Hb targets, other ESA exposures or rare and other long-term harms are absent from this summary. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Direct evidence for other populations, goals and rare harms remains unverified.	Direct population-, target- and exposure-specific materials and safety follow-up	Proposal: If direct materials are supplied, distinguish the selected claim from other indication and harm questions.
41	Partly verified	Full text not readStored summary read	N41 · Evidence conditionWhat were DAHANCA's mixed support, device or drug supply and roles?Required	Danish Cancer Society and Amgen support, Amgen's free trial drug/Aranesp and main GCP and quality-control costs are preserved. The original account says the trial was investigator driven, Amgen had no design, conduct, collection or analysis role and offered no comments despite a manuscript-comment opportunity. R01	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Original contracts, complete declarations and direct current role comparisons remain unread.	Original sponsorship and supply, roles, contracts and data access and COI declarations	Proposal: If original declarations are supplied, distinguish support and supply from each actual operational role.
42	Partly verified	Full text not readStored summary read	N42 · Evidence conditionWhat are funding and author relationships in other trials and the review?Supplementary	Original accounts record F. Hoffmann-La Roche support for ENHANCE, NCI/Ortho Biotech support for RTOG and mixed public and company funding of the review's included trials. Detailed company and investigator roles and the review's own declarations are absent. R02 R03 R04	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Detailed roles, the review's own funding and COIs and investigator and population overlap remain unverified.	Report-specific sponsorship and supply, author, analysis and manuscript roles and review declarations	Proposal: If original declarations and inclusion tables are supplied, record roles, families and funding by report.
43	Partly verified	Full text not readStored summary read	N43 · Evidence conditionAre original repeated refutation and unique trial and repeated-harm counts established?Required	The original parent describes repeated refutation/RX across three different drugs and independent trials. This is preserved, but review inclusion, trial identities, replications and follow-up were not exhaustively compared, so unique counts and independence are not certified. R01 R02 R03 R04	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Unique trial totals, participant and event sums and independent repeated-harm counts remain undetermined.	Unique families, inclusion and follow-up, investigators and funding and event and population lists	Proposal: If original lists are supplied, link same, different and uncertain families and repeated citations.
44	Partly verified	Full text not readStored summary read	N44 · Evidence conditionAre original dates, corrections, Korean and English texts and empty values preserved?Required	Date 2026-08-26, empty corrections and deliberation, Korean and English texts and parent-axis true, false, unrecorded and empty-string values are preserved. R01 R02 R03 R04	Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Separate evidence-cutoff and facet fields are absent; no latest correction, retraction or regulatory search was performed.	Original dates, corrections and languages and current input and update scope	Proposal: If actual update materials are supplied, distinguish the complete original version from the correction event.

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44 itemsWhat the statuses mean

Assessment scope

Stored-material review date: Not recorded
Original evidence cut-off: 2026-08-26
Scope actually checked: Existing review summaries and stored records of methodological application. Full papers, supplements, registrations, plans and original data were not read.
What the dates mean: This is the date the stored materials were checked, not the date of a new search of the clinical literature.
Population: Head-and-neck squamous-cell carcinoma radiotherapy; original DAHANCA inclusion of Hb below 14.0 g/dL; stage and detailed eligibility remain unverified
Ingredient, formulation and route: Original studies of ESA anemia correction during radiotherapy; individual trial conditions for darbepoetin, epoetin beta and epoetin alfa
Dose: Historical weekly darbepoetin exposure in DAHANCA; actual amount, route, target and adherence remain unverified. This is not medication, anticancer, anemia-correction or radiotherapy guidance.
Comparator: Original trial-specific controls: ENHANCE placebo, RTOG ESA added or not added, and radiotherapy alone in the review; specific concomitant treatments remain unverified
Measured outcome: Existing question of improved locoregional tumor control; original time to failure and five-year cumulative failure are lower-is-better and showed worsening. Survival and Hb are separate outcomes.
Duration: Original DAHANCA five-year cumulative outcomes and interim stopping; RTOG three- and five-year outcomes and follow-up and review-version context; detailed individual and endpoint follow-up remain unverified
Questions outside this scope: Converting Hb correction into improved tumor control or survival; Reversing failure-rate or HR direction into benefit; Adding RTOG follow-up or review participants as independent groups; Identical effects or harms in other cancers, populations or Hb targets, kidney disease or preterm-infant indications; Current FDA-approval certification or medication, radiotherapy, anemia-correction or anticancer-treatment instructions

Evidence and sources

The links below lead to the sources. A link alone does not mean the original source was read or its latest publication status verified.

R01 · Overgaard J, Hoff CM, Hansen HS, et al. DAHANCA 10—Effect of darbepoetin alfa and radiotherapy in squamous cell carcinoma of the head and neck. Radiother Oncol. 2018;127:12-19. PMID: 29523409.

PubMed

Material type: DAHANCA 10 report of an open-label phase 3 darbepoetin-radiotherapy trial
Materials actually read: Summary read; external abstracts and full texts not read
Findings recorded in the stored summary: 522 randomized/513 evaluable (254/259). Five-year cumulative failure 47% versus 34%, HR 1.53 (95% CI 1.16–2.02); EFS HR 1.36 (1.09–1.69), disease-specific death 1.43 (1.08–1.90) and overall death 1.30 (1.02–1.64) point in the original harmful direction. Original history records interim stopping at 522 of planned 600.
Record level: Not recorded
Study overlap and independent replication: DAHANCA's same population, failure, survival, Hb, safety, interim and follow-up context; original independence statements are historical and do not currently certify unique families. ENHANCE's original drug, population, locoregional PFS and survival context is not added to other trial values or denominators. The two initial and long-term RTOG 99-03 PMIDs form the original same-trial report group; 148 participants, durations and endpoints are not added as new independent populations. The five-RCT/1397-participant review's inclusion version, contributions and overlap remain unread and are not counted independently alongside original trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Stored summary	Local preserved copy	Local preserved summary acquired	Summary read	Relevant evidence, bibliography and Korean and English context from the complete specified preserved summary were linked for production. External full texts were not read.
External abstract	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Only original bibliography links were preserved; current access, reading and link verification were not performed.
External full text or follow-up report	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Original links connect bibliographic identities and do not indicate direct full-text acquisition or reading. Follow-up of the same trial is not a new independent population.
External registration	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	The original registration statement that it predates registration requirements and is absent was preserved; current registration existence or absence was not directly queried or certified.
Required materials: protocol or review plan	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Required scope: failure and survival definitions, flow and censoring, interim plans and adjudication, exposure and targets, safety and Amgen roles; original-material existence, public availability and acquisition remain unverified.
Required materials: SAP, interim or synthesis analyses	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Endpoint hierarchy and models, interim analysis, censoring and missingness, or review coding, inclusion and synthesis methods remain unread.
Required materials: results, denominators, safety and regulation	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Direct original endpoint- and timepoint-specific results, flow, safety and relevant regulatory materials are needed; FDA links or contents were not newly queried or created.
Required materials: funding and COI	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Report-specific sponsorship, free drug, operational, analysis and manuscript roles and review declarations were not directly read.

R02 · Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy. Lancet. 2003;362:1255-1260. PMID: 14575968.

PubMed

Material type: ENHANCE epoetin-beta double-blind placebo-controlled report
Materials actually read: Summary read; external abstracts and full texts not read
Findings recorded in the stored summary: Original notation: 351 (180/171), ITT. Locoregional PFS adjusted RR 1.62 (95% CI 1.22–2.14), P=.0008; survival RR 1.39 (1.05–1.84), in the original harmful direction. Details of models, exposure and intervals remain unread.
Record level: Not recorded
Study overlap and independent replication: DAHANCA's same population, failure, survival, Hb, safety, interim and follow-up context; original independence statements are historical and do not currently certify unique families. ENHANCE's original drug, population, locoregional PFS and survival context is not added to other trial values or denominators. The two initial and long-term RTOG 99-03 PMIDs form the original same-trial report group; 148 participants, durations and endpoints are not added as new independent populations. The five-RCT/1397-participant review's inclusion version, contributions and overlap remain unread and are not counted independently alongside original trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Stored summary	Local preserved copy	Local preserved summary acquired	Summary read	Relevant evidence, bibliography and Korean and English context from the complete specified preserved summary were linked for production. External full texts were not read.
External abstract	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Only original bibliography links were preserved; current access, reading and link verification were not performed.
External full text or follow-up report	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Original links connect bibliographic identities and do not indicate direct full-text acquisition or reading. Follow-up of the same trial is not a new independent population.
External registration	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	The original registration statement that it predates registration requirements and is absent was preserved; current registration existence or absence was not directly queried or certified.
Required materials: protocol or review plan	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Required scope: PFS and survival definitions, actual denominators and ITT, adjustment, exposure and targets, safety and Roche roles; original-material existence, public availability and acquisition remain unverified.
Required materials: SAP, interim or synthesis analyses	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Endpoint hierarchy and models, interim analysis, censoring and missingness, or review coding, inclusion and synthesis methods remain unread.
Required materials: results, denominators, safety and regulation	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Direct original endpoint- and timepoint-specific results, flow, safety and relevant regulatory materials are needed; FDA links or contents were not newly queried or created.
Required materials: funding and COI	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Report-specific sponsorship, free drug, operational, analysis and manuscript roles and review declarations were not directly read.

R03 · Machtay M, Pajak TF, Suntharalingam M, et al. Radiotherapy with or without erythropoietin for anemic patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2007. PMID: 17716826; long-term follow-up PMID: 25670542.

PubMed

Material type: Preserved RTOG 99-03 initial and long-term report group from the same trial
Materials actually read: Summary read; external abstracts and full texts not read
Findings recorded in the stored summary: 148 randomized. Three-year failure 44% versus 36% (P=.56), five-year failure 46.2% versus 39.4% (P=.42), OS 36.9% versus 38.2% (P=.54), originally described as no benefit. Initial PMID 17716826 and long-term PMID 25670542 concern the same trial and are not added as new populations.
Record level: Not recorded
Study overlap and independent replication: DAHANCA's same population, failure, survival, Hb, safety, interim and follow-up context; original independence statements are historical and do not currently certify unique families. ENHANCE's original drug, population, locoregional PFS and survival context is not added to other trial values or denominators. The two initial and long-term RTOG 99-03 PMIDs form the original same-trial report group; 148 participants, durations and endpoints are not added as new independent populations. The five-RCT/1397-participant review's inclusion version, contributions and overlap remain unread and are not counted independently alongside original trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Stored summary	Local preserved copy	Local preserved summary acquired	Summary read	Relevant evidence, bibliography and Korean and English context from the complete specified preserved summary were linked for production. External full texts were not read.
External abstract	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Only original bibliography links were preserved; current access, reading and link verification were not performed.
External full text or follow-up report	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Original links connect bibliographic identities and do not indicate direct full-text acquisition or reading. Follow-up of the same trial is not a new independent population.
External registration	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Only original string NCT00004917 was preserved; registration contents, timing and plans remain unread.
Required materials: protocol or review plan	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Required scope: initial and follow-up flow, endpoint- and duration-specific denominators and CIs, exposure and analyses and NCI/Ortho roles; original-material existence, public availability and acquisition remain unverified.
Required materials: SAP, interim or synthesis analyses	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Endpoint hierarchy and models, interim analysis, censoring and missingness, or review coding, inclusion and synthesis methods remain unread.
Required materials: results, denominators, safety and regulation	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Direct original endpoint- and timepoint-specific results, flow, safety and relevant regulatory materials are needed; FDA links or contents were not newly queried or created.
Required materials: funding and COI	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Report-specific sponsorship, free drug, operational, analysis and manuscript roles and review declarations were not directly read.

R04 · Bohlius J, Schmidlin K, Brillant C, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane review subgroup of head and neck radiotherapy trials. PMID: 19588382.

PubMed

Material type: Systematic-review and meta-analysis report of five RCTs in head-and-neck radiotherapy
Materials actually read: Summary read; external abstracts and full texts not read
Findings recorded in the stored summary: Original review size: five RCTs/1,397 participants. OS Peto OR 0.73 (95% CI 0.58–0.91), locoregional PFS OR 0.63 (0.49–0.80), originally favoring radiotherapy alone. Inclusion, contributions, timing and independent-population counts remain unverified.
Record level: Not recorded
Study overlap and independent replication: DAHANCA's same population, failure, survival, Hb, safety, interim and follow-up context; original independence statements are historical and do not currently certify unique families. ENHANCE's original drug, population, locoregional PFS and survival context is not added to other trial values or denominators. The two initial and long-term RTOG 99-03 PMIDs form the original same-trial report group; 148 participants, durations and endpoints are not added as new independent populations. The five-RCT/1397-participant review's inclusion version, contributions and overlap remain unread and are not counted independently alongside original trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Stored summary	Local preserved copy	Local preserved summary acquired	Summary read	Relevant evidence, bibliography and Korean and English context from the complete specified preserved summary were linked for production. External full texts were not read.
External abstract	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Only original bibliography links were preserved; current access, reading and link verification were not performed.
External full text or follow-up report	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Original links connect bibliographic identities and do not indicate direct full-text acquisition or reading. Follow-up of the same trial is not a new independent population.
External registration	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	The original registration value not applicable was preserved; current registration existence or absence was not directly queried or certified.
Required materials: protocol or review plan	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Required scope: version, inclusion and contributions, unique families, OR coding, synthesis, heterogeneity, sponsorship and COI; original-material existence, public availability and acquisition remain unverified.
Required materials: SAP, interim or synthesis analyses	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Endpoint hierarchy and models, interim analysis, censoring and missingness, or review coding, inclusion and synthesis methods remain unread.
Required materials: results, denominators, safety and regulation	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Direct original endpoint- and timepoint-specific results, flow, safety and relevant regulatory materials are needed; FDA links or contents were not newly queried or created.
Required materials: funding and COI	Current public availability and detailed existence remain unverified	Access not attempted; not obtained	Not read	Report-specific sponsorship, free drug, operational, analysis and manuscript roles and review declarations were not directly read.

Report counts versus independent study counts

DAHANCA's same population, failure, survival, Hb, safety, interim and follow-up context; original independence statements are historical and do not currently certify unique families. ENHANCE's original drug, population, locoregional PFS and survival context is not added to other trial values or denominators. The two initial and long-term RTOG 99-03 PMIDs form the original same-trial report group; 148 participants, durations and endpoints are not added as new independent populations. The five-RCT/1397-participant review's inclusion version, contributions and overlap remain unread and are not counted independently alongside original trials.

Review criteria

Version 1.0 · Criteria record date 2026-10-06. These are Chamgap's own application conditions, informed by the referenced methods. They do not constitute official assessment-tool certification or a new efficacy score.

N01 · Is the selected original question improved locoregional tumor control?

Required materials and conditions: Link selected and parent claims, disease, exposure and failure direction
Conditions for verification: Preserve both the original positive question and the actual direction of its original results.
Requirement and applicability: Required
Application exceptions: Do not arbitrarily rename the improvement question as a harm question or create a new verdict or split.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Is the selected original question improved locoregional tumor control?
Referenced methods: M03 §3.1, §3.2.1–3.2.4 question-clarification principles; detailed separation rules are our own design / M03 §3.2.4; our own extension boundary

N02 · Are the subclaim's grade F and note separate from parent F12 and axes?

Required materials and conditions: Locations of actual and absent subclaim fields and original parent values
Conditions for verification: Distinguish the actual subclaim grade F from the parent verdict's scope.
Requirement and applicability: Required
Application exceptions: Do not uniformly assign D to subclaims or copy parent 12 points, RX, I1, E-, B2/C0 as distinct subclaim values.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are the subclaim's grade F and note separate from parent F12 and axes?
Referenced methods: M03 §3.1, §3.2.1–3.2.4 question-clarification principles; detailed separation rules are our own design / M04 §4.5, §4.6.3; current material-conversion limits reflect review scope and our own design

N03 · Do repeated refutation, design limitations and cross-checking constitute current review?

Required materials and conditions: Korean and English wording, axes, verdict, corrections and methodological statements
Conditions for verification: Separate original history from incomplete current content review.
Requirement and applicability: Required
Application exceptions: Do not inherit RX, the true large-hard-endpoint RCT indication or historical independence and cross-checking as current review or independence certification.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Do repeated refutation, design limitations and cross-checking constitute current review?
Referenced methods: M04 §4.5, §4.6.3; current material-conversion limits reflect review scope and our own design / M08 §8.1–8.2.3; our own application

N04 · Which materials were actually read, and which external materials remain unread?

Required materials and conditions: Acquisition and reading scope for preserved summaries and each external material
Conditions for verification: Keep summary reading and external unread status separate for each material.
Requirement and applicability: Required
Application exceptions: Do not convert the presence of a URL or a statement about original-paper roles into current full-text reading, link verification or failed access.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Which materials were actually read, and which external materials remain unread?
Referenced methods: M04 §4.5–4.6 material-collection and selection principles; separation of access and reading and hyperlink rules are our own design / M04 §4.5, §4.6.3; current material-conversion limits reflect review scope and our own design

N05 · How are trials, the review and initial and follow-up reports linked?

Required materials and conditions: Original bibliography, review inclusion, initial and long-term reports and participant relationships
Conditions for verification: Distinguish preserved report groups from undetermined unique totals and other indications.
Requirement and applicability: Required
Application exceptions: Do not add the review, original trials, two RTOG PMIDs or 2925 as new independent trials or participants.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: How are trials, the review and initial and follow-up reports linked?
Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort and outcome linking is our own application / M04 §4.6.1–4.6.2, M15 §15.3.1; our own application

N06 · What were DAHANCA's population and Hb eligibility conditions?

Required materials and conditions: Stage, site, inclusion and exclusion, Hb, anemia cause and baseline risk
Conditions for verification: Record original population and Hb eligibility along with gaps in detailed conditions.
Requirement and applicability: Required
Application exceptions: Do not reuse the Hb eligibility threshold as an effect for all severe-anemia or other-cancer populations.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What were DAHANCA's population and Hb eligibility conditions?
Referenced methods: M03 §3.2.1; detailed population conditions are our own design / M03 §3.2.1–3.2.4; dose, persistence and effect-modification details are our own design

N07 · What were darbepoetin exposure, goals and hematologic response in the trial?

Required materials and conditions: Nominal and actual drug exposure, Hb target, changes and discontinuation
Conditions for verification: Distinguish historical drug conditions from gaps in direct exposure and targets.
Requirement and applicability: Required
Application exceptions: Do not write the historical weekly exposure as medication, anemia-correction, anticancer or radiotherapy-selection instructions.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What were darbepoetin exposure, goals and hematologic response in the trial?
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and assessment adaptations are our own design / M03 §3.2.3, M08 §8.2.2–8.2.3; our own application

N08 · What were control radiotherapy and shared or concurrent cancer treatments?

Required materials and conditions: Trial-specific controls, radiotherapy plans and shared or concomitant cancer and anemia treatment
Conditions for verification: Separate original comparison wording from gaps in detailed conditions.
Requirement and applicability: Required
Application exceptions: Do not use the review's control label to certify that every trial had no concomitant treatment.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What were control radiotherapy and shared or concurrent cancer treatments?
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and assessment adaptations are our own design / M03 §3.2.3, M08 §8.2.2–8.2.3; our own application / M19 §19.2.2–19.2.4 design considerations; detailed confounding records are our own design

N09 · Are planned 600, randomized 522 and evaluable 513 different stages?

Required materials and conditions: Allocation and evaluation flow by arm, correspondence of 254/259 to arms, exclusions and missingness
Conditions for verification: Distinguish original stage-specific denominators from unverified flow.
Requirement and applicability: Required
Application exceptions: Do not subtract counts to calculate attrition counts or rates or use planned 600 as the actual analysis population.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are planned 600, randomized 522 and evaluable 513 different stages?
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design / M08 §8.2.2, M15 §15.3.1; our own application

N10 · What are the locoregional-failure time, five-year values and HR?

Required materials and conditions: Failure definition, timepoint and time, denominator, HR model and interval
Conditions for verification: Attribute the original endpoint, 47/34%, HR and 95% CI to the relevant comparison.
Requirement and applicability: Required
Application exceptions: Do not calculate new risk differences, CIs or P values from original proportions or HRs.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are the locoregional-failure time, five-year values and HR?
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design / M15 §15.3.1–15.3.3; our own application

N11 · How should lower-is-better failure and the improvement question be read?

Required materials and conditions: Endpoint direction and relationship between question and result
Conditions for verification: Clearly distinguish the original improvement question from the observed worsening direction.
Requirement and applicability: Required
Application exceptions: Do not turn increased failure into improved tumor control or a positive benefit.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: How should lower-is-better failure and the improvement question be read?
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M03 §3.2.4; our own extension boundary

N12 · Are the five-year cumulative proportion and time-to-failure HR the same measure?

Required materials and conditions: Cumulative estimation, censoring, HR estimand, time and competing events
Conditions for verification: Distinguish different original measures and gaps in their models.
Requirement and applicability: Required
Application exceptions: Do not convert 47/34 or the HR into a new risk ratio, effect size or individual probability.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are the five-year cumulative proportion and time-to-failure HR the same measure?
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M08 §8.2.2, M15 §15.3.1; our own application / M15 §15.3.1–15.3.3; our own application

N13 · What are the actual analysis and risk denominators for locoregional outcomes?

Required materials and conditions: Endpoint-specific analysis and risk populations, events and people, censoring and missingness
Conditions for verification: Record the original evaluation size and gaps in direct outcome denominators.
Requirement and applicability: Required
Application exceptions: Do not copy evaluable 513 into every timepoint, survival or safety denominator or back-calculate event counts.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are the actual analysis and risk denominators for locoregional outcomes?
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design / M08 §8.2.2, M15 §15.3.1; our own application

N14 · What was the actual scope of open-label design and central blinded review?

Required materials and conditions: Failure diagnosis and adjudication, imaging and clinical pathways and blinding by role
Conditions for verification: Separate original open-label and review limitations from direct details.
Requirement and applicability: Required
Application exceptions: Do not expand the absence of uniform central blinded review into an absence of all adjudication or examinations.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What was the actual scope of open-label design and central blinded review?
Referenced methods: M08 Table 8.2.a, M03 §3.2.4; our own application / M08 §8.1–8.2.3; our own application

N15 · What is known about randomization, allocation concealment and baseline balance?

Required materials and conditions: Allocation procedures, concealment, baseline and stratification factors and treatment balance
Conditions for verification: Separate original design from gaps in direct procedures.
Requirement and applicability: Required
Application exceptions: Do not certify fulfillment of all methodological conditions from the randomized label, B2 or a past verdict.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is known about randomization, allocation concealment and baseline balance?
Referenced methods: M08 §8.1–8.2.3; our own application / M03 §3.2.1; detailed population conditions are our own design

N16 · What does early stopping at the planned interim analysis preserve?

Required materials and conditions: Interim timing and thresholds, committee, alpha, stopping and subsequent follow-up
Conditions for verification: Preserve the original stopping event and direct gaps in planning and follow-up.
Requirement and applicability: Required
Application exceptions: Do not turn the original planned-analysis wording into direct certification of advance planning or an exact bias magnitude.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What does early stopping at the planned interim analysis preserve?
Referenced methods: M08 Table 8.2.a, M04 §4.6.3; our own application / M08 §8.2.2, M15 §15.3.1; our own application / M15 §15.3.1–15.3.3; our own application

N17 · Does hematologic correction constitute a tumor-control benefit?

Required materials and conditions: Hematologic response, achieved Hb, denominator, tumor oxygenation and direct events
Conditions for verification: Preserve original hematologic statements separately from direct clinical worsening.
Requirement and applicability: Required
Application exceptions: Do not treat increased Hb as a guarantee of oxygenation, tumor-control or survival improvement.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Does hematologic correction constitute a tumor-control benefit?
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M03 §3.2.4; our own extension boundary

N18 · What is the original event-free-survival value?

Required materials and conditions: EFS definition and components, denominator, HR model and interval confidence level
Conditions for verification: Keep the original EFS HR, interval and direction separate.
Requirement and applicability: Supplementary
Application exceptions: Do not automatically copy locoregional-failure values or its 95% CI designation into EFS.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is the original event-free-survival value?
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M03 §3.2.4; our own extension boundary

N19 · What is the disease-specific-death result?

Required materials and conditions: Cause-of-death adjudication, events and time, denominator, model and interval
Conditions for verification: Separate the original disease-specific HR from gaps in direct definitions.
Requirement and applicability: Supplementary
Application exceptions: Do not fill disease-specific death with another endpoint's HR or 95% designation.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is the disease-specific-death result?
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M03 §3.2.4; our own extension boundary

N20 · What is the original overall-death HR?

Required materials and conditions: Overall death, risk population and denominator, time, model and interval
Conditions for verification: Preserve original overall-death values and gaps.
Requirement and applicability: Supplementary
Application exceptions: Do not calculate death counts, absolute-risk differences or new intervals from the original HR.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is the original overall-death HR?
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M03 §3.2.4; our own extension boundary

N21 · Is the sibling survival-improvement question separate from the main tumor question?

Required materials and conditions: Existing sibling question, endpoint definitions and denominators and original-result links
Conditions for verification: Distinguish original survival context from the selected question.
Requirement and applicability: Supplementary
Application exceptions: Do not count the sibling row as a new trial or participant group or copy failure values into survival outcomes.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Is the sibling survival-improvement question separate from the main tumor question?
Referenced methods: M03 §3.1, §3.2.1–3.2.4 question-clarification principles; detailed separation rules are our own design / M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M03 §3.2.4; our own extension boundary

N22 · What are the details of follow-up, treatment deviations, missingness and censoring?

Required materials and conditions: Endpoint-specific flow, follow-up and censoring, treatment deviations and missing-data handling
Conditions for verification: Record direct gaps in original flow and time.
Requirement and applicability: Required
Application exceptions: Do not calculate or infer new attrition or analysis rules from differences in allocation and evaluation counts.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are the details of follow-up, treatment deviations, missingness and censoring?
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design / M08 §8.2.2, M15 §15.3.1; our own application / M19 §19.1.2–19.2.4, M04 §4.6.3; our own application

N23 · What history underlies the original registration-absence statements?

Required materials and conditions: Original registration, timing, contemporaneous records and plans and changes
Conditions for verification: Distinguish original values from the current unqueried scope.
Requirement and applicability: Required
Application exceptions: Do not turn the historical absence wording into current certification of exhaustive registry absence or a new identifier.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What history underlies the original registration-absence statements?
Referenced methods: M04 §4.5–4.6 material-collection and selection principles; separation of access and reading and hyperlink rules are our own design / M04 §4.5, §4.6.3; current material-conversion limits reflect review scope and our own design / M08 Table 8.2.a, M04 §4.6.3; our own application

N24 · Were prior endpoints, interim plans and the hierarchy of multiple outcomes read?

Required materials and conditions: Original plans, prior hierarchy, interim and final testing and changes
Conditions for verification: Separate original roles from gaps in planning details.
Requirement and applicability: Required
Application exceptions: Do not certify every prior definition solely from the original primary-endpoint or planned-analysis labels.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Were prior endpoints, interim plans and the hierarchy of multiple outcomes read?
Referenced methods: M08 Table 8.2.a, M04 §4.6.3; our own application / M04 §4.5–4.6 material-collection and selection principles; separation of access and reading and hyperlink rules are our own design

N25 · What are the clinical thresholds, individual effects and subgroups?

Required materials and conditions: Prior importance thresholds and subgroup hypotheses, interactions, denominators and intervals
Conditions for verification: Record overall original results and gaps in subgroup effects and clinical importance.
Requirement and applicability: Supplementary
Application exceptions: Do not copy original effects into every stage, Hb target, dose or individual outcome.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are the clinical thresholds, individual effects and subgroups?
Referenced methods: M15 §15.3.1–15.3.3; our own application / M03 §3.2.1–3.2.4; dose, persistence and effect-modification details are our own design

N26 · What are ENHANCE's original population, design and RR results?

Required materials and conditions: PFS and survival definitions, adjusted model, actual denominators, ITT and intervals
Conditions for verification: Preserve each original RR, interval and P value and trial-specific denominator and hierarchy.
Requirement and applicability: Supplementary
Application exceptions: Do not change original RRs into DAHANCA HRs or probabilities of improvement.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are ENHANCE's original population, design and RR results?
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M08 §8.1–8.2.3; our own application

N27 · How do epoetin beta, epoetin alfa and darbepoetin exposures differ?

Required materials and conditions: Drug-specific formulation, amount and targets, shared and different treatments and populations
Conditions for verification: Record shared claim context together with actual drug and exposure differences.
Requirement and applicability: Supplementary
Application exceptions: Do not fill different drugs or targets with the same dose or conditions or extend them to every other indication.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: How do epoetin beta, epoetin alfa and darbepoetin exposures differ?
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and assessment adaptations are our own design / M03 §3.2.3, M08 §8.2.2–8.2.3; our own application / M03 §3.2.1–3.2.4; dose, persistence and effect-modification details are our own design

N28 · What are RTOG's initial and long-term endpoint values?

Required materials and conditions: Timepoint-specific failure and OS, denominators, estimates, CIs and analysis plans
Conditions for verification: Keep original timepoints, proportions and P values attached to their respective endpoints.
Requirement and applicability: Supplementary
Application exceptions: Do not turn nonsignificance into zero effect, equivalence or guaranteed individual survival.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are RTOG's initial and long-term endpoint values?
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design

N29 · Do the two RTOG PMIDs refer to reports of the same trial?

Required materials and conditions: Initial and follow-up populations, timepoints and analysis and report relationships
Conditions for verification: Preserve the original report group, bibliography and same-population relationship.
Requirement and applicability: Supplementary
Application exceptions: Do not add two PMIDs or timepoints as two groups of 148 participants or independent replications.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Do the two RTOG PMIDs refer to reports of the same trial?
Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort and outcome linking is our own application / M04 §4.6.1–4.6.2, M15 §15.3.1; our own application

N30 · Can the five-RCT, 1,397-participant review be added to original trials?

Required materials and conditions: Inclusion and contribution lists, trial identities, populations and timepoints and overlap
Conditions for verification: Distinguish original review counts from undetermined unique totals.
Requirement and applicability: Supplementary
Application exceptions: Do not add review 1,397 and individual trials or follow-up to create new participant or trial totals.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Can the five-RCT, 1,397-participant review be added to original trials?
Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort and outcome linking is our own application / M04 §4.6.1–4.6.2, M15 §15.3.1; our own application / M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design

N31 · What is the event direction of the review's ORs?

Required materials and conditions: Review event and success coding, models and endpoint-specific contributions and intervals
Conditions for verification: Preserve the original review direction, measures and intervals at their stated level.
Requirement and applicability: Supplementary
Application exceptions: Do not reverse OR<1 into reduced death or failure with ESA or convert it into an HR or RR.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is the event direction of the review's ORs?
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M15 §15.3.1–15.3.3; our own application

N32 · What are the review's timing, subsets, heterogeneity and direct comparisons?

Required materials and conditions: Review version, inclusion timing, endpoint subsets, synthesis, heterogeneity and conditions
Conditions for verification: Preserve original dates and bibliography and gaps in actual inclusion.
Requirement and applicability: Supplementary
Application exceptions: Do not assume every recent report was included in the review or arbitrarily correct years or identities.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are the review's timing, subsets, heterogeneity and direct comparisons?
Referenced methods: M04 §4.6.1–4.6.2, M15 §15.3.1; our own application / M08 §8.2.2, M15 §15.3.1; our own application / M03 §3.2.1–3.2.4; dose, persistence and effect-modification details are our own design

N33 · Are repeated refutation in the same indication and other goals distinguished?

Required materials and conditions: Direct questions, exposures and endpoints for each indication and goal
Conditions for verification: Preserve only the original link context for another goal and do not create treatment-selection instructions.
Requirement and applicability: Supplementary
Application exceptions: Do not merge 2925 as tumor-control benefit, safety evidence or a separate anticancer trial here.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are repeated refutation in the same indication and other goals distinguished?
Referenced methods: M03 §3.2.1; detailed population conditions are our own design / M03 §3.2.2–3.2.3; reverse-direction labeling and assessment adaptations are our own design / M03 §3.2.4; our own extension boundary

N34 · What is the original statement of no differences in ancillary safety?

Required materials and conditions: Safety definitions and collection, individual events and denominators, estimates and intervals
Conditions for verification: Preserve both original ancillary-safety statements and direct clinical worsening.
Requirement and applicability: Supplementary
Application exceptions: Do not turn unverified differences into zero events, equivalence of all safety outcomes or harmlessness.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is the original statement of no differences in ancillary safety?
Referenced methods: M19 §19.1.2–19.2.4; detailed distinctions are our own design / M19 §19.2.2–19.2.4, M03 §3.2.3; our own application / M19 §19.1.2–19.2.4; our own application / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design

N35 · Are major tumor and survival harms separate from safety collection?

Required materials and conditions: Clinical-harm and safety endpoints, collection and adjudication, severity and discontinuation
Conditions for verification: Distinguish endpoint-specific harm from gaps in complete collection.
Requirement and applicability: Supplementary
Application exceptions: Do not erase demonstrated tumor or survival harm based on no differences in ancillary safety.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are major tumor and survival harms separate from safety collection?
Referenced methods: M19 §19.1.2–19.2.4; detailed distinctions are our own design / CHAMGAP's own interpretation boundary. M19 principles are referenced; no official causality tool was run / M19 §19.1.2–19.2.4; our own application

N36 · What are harm-event, participant and time denominators and timepoints?

Required materials and conditions: Safety-specific denominators and durations, event timing and treatment and follow-up discontinuation
Conditions for verification: Separate original clinical context from gaps in safety time and denominators.
Requirement and applicability: Supplementary
Application exceptions: Do not copy 513/522 or five-year figures as actual denominators or duration for every harm.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are harm-event, participant and time denominators and timepoints?
Referenced methods: M19 §19.2 design-specific harm questions; temporal-relationship details are our own design / M19 §19.1.2–19.2.4; our own application / M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design

N37 · What is known about baseline cancer risk, concurrent treatments and alternative attribution?

Required materials and conditions: Baseline and concurrent exposures, event attribution, adjustment and alternative explanations
Conditions for verification: Separate original comparisons from gaps in attribution and mechanisms.
Requirement and applicability: Supplementary
Application exceptions: Do not turn population-level harmful direction into established causes or mechanisms for individual patients.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is known about baseline cancer risk, concurrent treatments and alternative attribution?
Referenced methods: M19 §19.2.2–19.2.4 design considerations; detailed confounding records are our own design / M03 §3.2.3, M08 §8.2.2–8.2.3; our own application

N38 · What is known about missing and complete safety and clinical follow-up?

Required materials and conditions: Safety and clinical flow, losses and omissions, reporting and censoring and sensitivity
Conditions for verification: Record original outcome limitations in follow-up and reporting.
Requirement and applicability: Supplementary
Application exceptions: Do not turn allocation and evaluation differences into absence of safety events or an exact bias magnitude.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is known about missing and complete safety and clinical follow-up?
Referenced methods: M19 §19.1.2–19.2.4, M04 §4.6.3; our own application / M08 §8.2.2, M15 §15.3.1; our own application

N39 · What is the scope of FDA warnings, original harm, current verification and causality?

Required materials and conditions: Original regulatory text and versions, indications and clinical-outcome and judgment scope
Conditions for verification: Separate original warnings and clinical harm from the current unqueried regulatory scope.
Requirement and applicability: Supplementary
Application exceptions: Do not create new regulatory links, certify current approval or provide treatment, medication, radiotherapy-selection or dosing instructions.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is the scope of FDA warnings, original harm, current verification and causality?
Referenced methods: CHAMGAP's own interpretation boundary. M19 principles are referenced; no official causality tool was run / M04 §4.5–4.6 material-collection and selection principles; separation of access and reading and hyperlink rules are our own design / M04 §4.5, §4.6.3; current material-conversion limits reflect review scope and our own design

N40 · Does this answer questions about other cancers, Hb targets, populations or long-term and rare harms?

Required materials and conditions: Direct population-, target- and exposure-specific materials and safety follow-up
Conditions for verification: Record original limits and gaps in safety and effect extensions.
Requirement and applicability: Supplementary
Application exceptions: Do not extend original repeated refutation to identical harm for every ESA indication and exposure.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Does this answer questions about other cancers, Hb targets, populations or long-term and rare harms?
Referenced methods: M19 §19.1.2–19.2.4; our own application / M03 §3.2.1–3.2.4; dose, persistence and effect-modification details are our own design / M03 §3.2.1; detailed population conditions are our own design

N41 · What were DAHANCA's mixed support, device or drug supply and roles?

Required materials and conditions: Original sponsorship and supply, roles, contracts and data access and COI declarations
Conditions for verification: Separate original support, supply and role context from currently unread declarations.
Requirement and applicability: Required
Application exceptions: Do not remove free-drug/GCP-cost or noninvolvement statements or upgrade I1 to current independence certification.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What were DAHANCA's mixed support, device or drug supply and roles?
Referenced methods: CHAMGAP's own independence and attribution conditions. Official methodological sections used in this pilot do not guarantee every detail of this item / M04 §4.6.1–4.6.2, M15 §15.3.1; our own application

N42 · What are funding and author relationships in other trials and the review?

Required materials and conditions: Report-specific sponsorship and supply, author, analysis and manuscript roles and review declarations
Conditions for verification: Preserve report-specific original funding and relationship gaps.
Requirement and applicability: Supplementary
Application exceptions: Do not certify current investigator or population independence solely from different supporting institutions.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are funding and author relationships in other trials and the review?
Referenced methods: CHAMGAP's own independence and attribution conditions. Official methodological sections used in this pilot do not guarantee every detail of this item / M04 §4.6.1–4.6.2 distinction between studies and reports; cohort and outcome linking is our own application

N43 · Are original repeated refutation and unique trial and repeated-harm counts established?

Required materials and conditions: Unique families, inclusion and follow-up, investigators and funding and event and population lists
Conditions for verification: Distinguish original history from unrecorded, undetermined unique counts.
Requirement and applicability: Required
Application exceptions: Do not add review, follow-up, the same population or endpoints as new independent trials or repeated events.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are original repeated refutation and unique trial and repeated-harm counts established?
Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort and outcome linking is our own application / M04 §4.6.1–4.6.2, M15 §15.3.1; our own application / M04 §4.6.1–4.6.2; harm-material adaptations are our own design

N44 · Are original dates, corrections, Korean and English texts and empty values preserved?

Required materials and conditions: Original dates, corrections and languages and current input and update scope
Conditions for verification: Record original history together with current production and incomplete content review.
Requirement and applicability: Required
Application exceptions: Do not borrow historical dates or cross-checking as current clinical-verification dates or certify exhaustive absence from empty corrections.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are original dates, corrections, Korean and English texts and empty values preserved?
Referenced methods: M04 §4.5, §4.6.3; current material-conversion limits reflect review scope and our own design / M03 §3.1, §3.2.1–3.2.4 question-clarification principles; detailed separation rules are our own design

Referenced methods and the sections actually reviewed

M03 · Cochrane Handbook 6.5 (2024), chapter updated 2023-08

Official methodology · §3.1, §3.2.1–3.2.3, MECIR C5/C7/C13

Referenced principle: Clearly record the question, eligibility conditions and reasons for changes, and distinguish variations in interventions.
Extent of review: 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

Official methodology · §4.5, §4.6.1–4.6.3, MECIR C42

Referenced principle: Distinguish studies from reports and link them; do not omit a study solely because results are unreported.
Extent of review: 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

Official methodology · §8.1–8.2.3, Table 8.2.a

Referenced principle: Define the outcome and effect of interest, then examine randomization, deviations, missing data, measurement and selective reporting.
Extent of review: 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

Official methodology · §15.2.4, §15.3.1–15.3.3

Referenced principle: Distinguish effect estimates, intervals, importance and applicability. Sample size alone does not determine precision.
Extent of review: 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

Official methodology · §19.1.2, §19.2.1–19.2.4

Referenced principle: Harm questions may require different designs, populations and follow-up from efficacy questions. Case reports do not establish incidence rates.
Extent of review: 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/material version 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.

The stored-material review date (Not recorded) and original evidence cut-off (2026-08-26) were retained unchanged.

Researcher downloads

These materials provide the same evidence, scope and verification status as this page.

View all item details

N01 · Is the selected original question improved locoregional tumor control?

Current findings: The selected existing question is improved locoregional tumor control. The parent describes harm from ESA anemia correction during head-and-neck radiotherapy. The question's improvement direction is distinguished from the observed worsening.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. The final count of independent claims remains undetermined.
Reason for missing information: The final count of independent claims remains undetermined.
Required materials and conditions: Link selected and parent claims, disease, exposure and failure direction
Materials to obtain first: Link selected and parent claims, disease, exposure and failure direction
Further research: Proposal: If the question actually changes, separately record its original wording and excluded scope.
Remaining uncertainty: Do not arbitrarily rename the improvement question as a harm question or create a new verdict or split. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Preserve both the original positive question and the actual direction of its original results.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Is the selected original question improved locoregional tumor control?
Application exceptions: Do not arbitrarily rename the improvement question as a harm question or create a new verdict or split.
Referenced methods: M03 §3.1, §3.2.1–3.2.4 question-clarification principles; detailed separation rules are our own design / M03 §3.2.4; our own extension boundary

Related sources R01

N02 · Are the subclaim's grade F and note separate from parent F12 and axes?

Current findings: Selected grade F and the note that five-year failure worsened to 47% versus 34% are preserved. Subclaim score, status and axes are absent and not recorded. Parent F12, safety Warning and axes belong to the parent.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. The original materials contain no distinct subclaim score, status or axes.
Reason for missing information: The original materials contain no distinct subclaim score, status or axes.
Required materials and conditions: Locations of actual and absent subclaim fields and original parent values
Materials to obtain first: Locations of actual and absent subclaim fields and original parent values
Further research: Proposal: If subclaim fields are actually added, distinguish the original version from the new event.
Remaining uncertainty: Do not uniformly assign D to subclaims or copy parent 12 points, RX, I1, E-, B2/C0 as distinct subclaim values. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Distinguish the actual subclaim grade F from the parent verdict's scope.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are the subclaim's grade F and note separate from parent F12 and axes?
Application exceptions: Do not uniformly assign D to subclaims or copy parent 12 points, RX, I1, E-, B2/C0 as distinct subclaim values.
Referenced methods: M03 §3.1, §3.2.1–3.2.4 question-clarification principles; detailed separation rules are our own design / M04 §4.5, §4.6.3; current material-conversion limits reflect review scope and our own design

Related sources R01

N03 · Do repeated refutation, design limitations and cross-checking constitute current review?

Current findings: The original parent describes F12 based on repeated refutation across three ESA trials, DAHANCA harm, early stopping at a planned interim analysis and open-label design. RX, cross-checking, true/false indications and empty values are historical records.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. No current RoB2/GRADE assessment, clinical reassessment or methodological certification was performed.
Reason for missing information: No current RoB2/GRADE assessment, clinical reassessment or methodological certification was performed.
Required materials and conditions: Korean and English wording, axes, verdict, corrections and methodological statements
Materials to obtain first: Korean and English wording, axes, verdict, corrections and methodological statements
Further research: Proposal: If new evidence is requested, separate the original version from the new update event.
Remaining uncertainty: Do not inherit RX, the true large-hard-endpoint RCT indication or historical independence and cross-checking as current review or independence certification. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Separate original history from incomplete current content review.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Do repeated refutation, design limitations and cross-checking constitute current review?
Application exceptions: Do not inherit RX, the true large-hard-endpoint RCT indication or historical independence and cross-checking as current review or independence certification.
Referenced methods: M04 §4.5, §4.6.3; current material-conversion limits reflect review scope and our own design / M08 §8.1–8.2.3; our own application

Related sources R01 R02 R03 R04

N04 · Which materials were actually read, and which external materials remain unread?

Current findings: The selection and complete preserved summary were read for production. External abstracts, full texts, registrations, plans, original FDA warnings and verdict 2925's page and links remain unread; access was not attempted.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. No search of current external contents, all recent literature or regulatory materials was performed.
Reason for missing information: No search of current external contents, all recent literature or regulatory materials was performed.
Required materials and conditions: Acquisition and reading scope for preserved summaries and each external material
Materials to obtain first: Acquisition and reading scope for preserved summaries and each external material
Further research: Proposal: If material and reading records are supplied, record only the actual level.
Remaining uncertainty: Do not convert the presence of a URL or a statement about original-paper roles into current full-text reading, link verification or failed access. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Keep summary reading and external unread status separate for each material.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Which materials were actually read, and which external materials remain unread?
Application exceptions: Do not convert the presence of a URL or a statement about original-paper roles into current full-text reading, link verification or failed access.
Referenced methods: M04 §4.5–4.6 material-collection and selection principles; separation of access and reading and hyperlink rules are our own design / M04 §4.5, §4.6.3; current material-conversion limits reflect review scope and our own design

Related sources R01 R02 R03 R04

N05 · How are trials, the review and initial and follow-up reports linked?

Current findings: DAHANCA 10, ENHANCE, the same-trial initial and long-term RTOG 99-03 report group and the five-RCT review are distinguished. The reference to 2925 concerns another indication and is not a report of this cancer trial.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Unique trial and participant totals and review inclusion and overlap were not directly verified.
Reason for missing information: Unique trial and participant totals and review inclusion and overlap were not directly verified.
Required materials and conditions: Original bibliography, review inclusion, initial and long-term reports and participant relationships
Materials to obtain first: Original bibliography, review inclusion, initial and long-term reports and participant relationships
Further research: Proposal: If original lists are supplied, link each report to the same, different or uncertain study family.
Remaining uncertainty: Do not add the review, original trials, two RTOG PMIDs or 2925 as new independent trials or participants. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Distinguish preserved report groups from undetermined unique totals and other indications.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: How are trials, the review and initial and follow-up reports linked?
Application exceptions: Do not add the review, original trials, two RTOG PMIDs or 2925 as new independent trials or participants.
Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort and outcome linking is our own application / M04 §4.6.1–4.6.2, M15 §15.3.1; our own application

Related sources R01 R02 R03 R04

N06 · What were DAHANCA's population and Hb eligibility conditions?

Current findings: The setting is head-and-neck squamous-cell carcinoma radiotherapy. The original DAHANCA condition included patients with Hb below 14.0 g/dL. Detailed stage, exact age and site and baseline anemia cause are absent from the summary.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Detailed stage, site, age, anemia cause and baseline risk remain unverified.
Reason for missing information: Detailed stage, site, age, anemia cause and baseline risk remain unverified.
Required materials and conditions: Stage, site, inclusion and exclusion, Hb, anemia cause and baseline risk
Materials to obtain first: Stage, site, inclusion and exclusion, Hb, anemia cause and baseline risk
Further research: Proposal: If original population tables are supplied, distinguish the actual population from gaps for other cancers and goals.
Remaining uncertainty: Do not reuse the Hb eligibility threshold as an effect for all severe-anemia or other-cancer populations. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Record original population and Hb eligibility along with gaps in detailed conditions.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What were DAHANCA's population and Hb eligibility conditions?
Application exceptions: Do not reuse the Hb eligibility threshold as an effect for all severe-anemia or other-cancer populations.
Referenced methods: M03 §3.2.1; detailed population conditions are our own design / M03 §3.2.1–3.2.4; dose, persistence and effect-modification details are our own design

Related sources R01

N07 · What were darbepoetin exposure, goals and hematologic response in the trial?

Current findings: The historical DAHANCA condition used weekly darbepoetin during radiotherapy. Exact dose, formulation, route, Hb target and stopping rules are absent from the summary.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Dose, route, actual adherence, achieved Hb and discontinuation details remain unverified.
Reason for missing information: Dose, route, actual adherence, achieved Hb and discontinuation details remain unverified.
Required materials and conditions: Nominal and actual drug exposure, Hb target, changes and discontinuation
Materials to obtain first: Nominal and actual drug exposure, Hb target, changes and discontinuation
Further research: Proposal: If original exposure records are supplied, record trial conditions and actual use and goals.
Remaining uncertainty: Do not write the historical weekly exposure as medication, anemia-correction, anticancer or radiotherapy-selection instructions. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Distinguish historical drug conditions from gaps in direct exposure and targets.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What were darbepoetin exposure, goals and hematologic response in the trial?
Application exceptions: Do not write the historical weekly exposure as medication, anemia-correction, anticancer or radiotherapy-selection instructions.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and assessment adaptations are our own design / M03 §3.2.3, M08 §8.2.2–8.2.3; our own application

Related sources R01

N08 · What were control radiotherapy and shared or concurrent cancer treatments?

Current findings: The original comparison is radiotherapy with an ESA added versus control. The review describes radiotherapy plus EPO versus radiotherapy alone. Specific radiotherapy and other concomitant treatments in each trial are absent from the summary.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Concomitant treatment, radiotherapy conditions and their balance remain unverified for each trial.
Reason for missing information: Concomitant treatment, radiotherapy conditions and their balance remain unverified for each trial.
Required materials and conditions: Trial-specific controls, radiotherapy plans and shared or concomitant cancer and anemia treatment
Materials to obtain first: Trial-specific controls, radiotherapy plans and shared or concomitant cancer and anemia treatment
Further research: Proposal: If original comparison materials are supplied, distinguish the added drug from shared and other treatments.
Remaining uncertainty: Do not use the review's control label to certify that every trial had no concomitant treatment. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Separate original comparison wording from gaps in detailed conditions.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What were control radiotherapy and shared or concurrent cancer treatments?
Application exceptions: Do not use the review's control label to certify that every trial had no concomitant treatment.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and assessment adaptations are our own design / M03 §3.2.3, M08 §8.2.2–8.2.3; our own application / M19 §19.2.2–19.2.4 design considerations; detailed confounding records are our own design

Related sources R01 R02 R03 R04

N09 · Are planned 600, randomized 522 and evaluable 513 different stages?

Current findings: DAHANCA's planned 600, 522 randomized at stopping and 513 evaluable (254/259) are separately preserved. Planning, allocation and evaluation represent different denominators.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Reasons for differences between allocation and evaluation, original arm correspondence and endpoint-denominator details remain externally unread.
Reason for missing information: Reasons for differences between allocation and evaluation, original arm correspondence and endpoint-denominator details remain externally unread.
Required materials and conditions: Allocation and evaluation flow by arm, correspondence of 254/259 to arms, exclusions and missingness
Materials to obtain first: Allocation and evaluation flow by arm, correspondence of 254/259 to arms, exclusions and missingness
Further research: Proposal: If original flow diagrams are supplied, record stages and inclusion rules by arm.
Remaining uncertainty: Do not subtract counts to calculate attrition counts or rates or use planned 600 as the actual analysis population. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Distinguish original stage-specific denominators from unverified flow.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are planned 600, randomized 522 and evaluable 513 different stages?
Application exceptions: Do not subtract counts to calculate attrition counts or rates or use planned 600 as the actual analysis population.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design / M08 §8.2.2, M15 §15.3.1; our own application

Related sources R01

N10 · What are the locoregional-failure time, five-year values and HR?

Current findings: The primary endpoint was time to locoregional failure. Original worsening results were five-year cumulative failure of 47% with darbepoetin versus 34% in controls, HR 1.53 (95% CI 1.16–2.02).
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Failure components and definition, population at risk, censoring and model remain unverified.
Reason for missing information: Failure components and definition, population at risk, censoring and model remain unverified.
Required materials and conditions: Failure definition, timepoint and time, denominator, HR model and interval
Materials to obtain first: Failure definition, timepoint and time, denominator, HR model and interval
Further research: Proposal: If original results and methods are supplied, link cumulative values to the time-to-event estimate.
Remaining uncertainty: Do not calculate new risk differences, CIs or P values from original proportions or HRs. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Attribute the original endpoint, 47/34%, HR and 95% CI to the relevant comparison.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are the locoregional-failure time, five-year values and HR?
Application exceptions: Do not calculate new risk differences, CIs or P values from original proportions or HRs.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design / M15 §15.3.1–15.3.3; our own application

Related sources R01

N11 · How should lower-is-better failure and the improvement question be read?

Current findings: The original reader answer explicitly states that lower locoregional failure is better. Failure of 47% versus 34% is originally described as worsening, rather than improvement.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Detailed endpoint-specific success and failure adjudication rules remain unverified.
Reason for missing information: Detailed endpoint-specific success and failure adjudication rules remain unverified.
Required materials and conditions: Endpoint direction and relationship between question and result
Materials to obtain first: Endpoint direction and relationship between question and result
Further research: Proposal: If original definitions are added, record actual directions and interpretations of other endpoints.
Remaining uncertainty: Do not turn increased failure into improved tumor control or a positive benefit. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Clearly distinguish the original improvement question from the observed worsening direction.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: How should lower-is-better failure and the improvement question be read?
Application exceptions: Do not turn increased failure into improved tumor control or a positive benefit.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M03 §3.2.4; our own extension boundary

Related sources R01

N12 · Are the five-year cumulative proportion and time-to-failure HR the same measure?

Current findings: Five-year cumulative locoregional failure and the time-to-failure HR are separate expressions. The original HR is not converted into a simple five-year risk ratio or difference in cumulative percentages.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Cumulative estimation, proportional hazards, competing risks and adjustment remain unverified.
Reason for missing information: Cumulative estimation, proportional hazards, competing risks and adjustment remain unverified.
Required materials and conditions: Cumulative estimation, censoring, HR estimand, time and competing events
Materials to obtain first: Cumulative estimation, censoring, HR estimand, time and competing events
Further research: Proposal: If original statistical methods are supplied, distinguish definitions of cumulative estimation and hazard comparisons.
Remaining uncertainty: Do not convert 47/34 or the HR into a new risk ratio, effect size or individual probability. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Distinguish different original measures and gaps in their models.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are the five-year cumulative proportion and time-to-failure HR the same measure?
Application exceptions: Do not convert 47/34 or the HR into a new risk ratio, effect size or individual probability.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M08 §8.2.2, M15 §15.3.1; our own application / M15 §15.3.1–15.3.3; our own application

Related sources R01

N13 · What are the actual analysis and risk denominators for locoregional outcomes?

Current findings: The original evaluable 513 (254/259) and five-year failure percentages are preserved. The five-year population at risk, follow-up, censoring and actual analysis denominators for each endpoint are absent from the summary.
Verification status: Unverified
Materials actually read: Summary read; external materials not read
Why unverified: Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Five-year risk population, event counts and endpoint-specific analyses and censoring remain unverified.
Reason for missing information: Five-year risk population, event counts and endpoint-specific analyses and censoring remain unverified.
Required materials and conditions: Endpoint-specific analysis and risk populations, events and people, censoring and missingness
Materials to obtain first: Endpoint-specific analysis and risk populations, events and people, censoring and missingness
Further research: Proposal: If original risk tables or flow diagrams are supplied, distinguish evaluation from timepoint and endpoint denominators.
Remaining uncertainty: Do not copy evaluable 513 into every timepoint, survival or safety denominator or back-calculate event counts. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Record the original evaluation size and gaps in direct outcome denominators.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are the actual analysis and risk denominators for locoregional outcomes?
Application exceptions: Do not copy evaluable 513 into every timepoint, survival or safety denominator or back-calculate event counts.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design / M08 §8.2.2, M15 §15.3.1; our own application

Related sources R01

N14 · What was the actual scope of open-label design and central blinded review?

Current findings: The original DAHANCA account describes open-label design and says locoregional failure was not uniformly adjudicated through central blinded imaging review for every patient.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Patient-specific adjudication pathways, partial central review and assessor and analyst roles remain unverified.
Reason for missing information: Patient-specific adjudication pathways, partial central review and assessor and analyst roles remain unverified.
Required materials and conditions: Failure diagnosis and adjudication, imaging and clinical pathways and blinding by role
Materials to obtain first: Failure diagnosis and adjudication, imaging and clinical pathways and blinding by role
Further research: Proposal: If original adjudication methods are supplied, record actual pathways and limitations by role.
Remaining uncertainty: Do not expand the absence of uniform central blinded review into an absence of all adjudication or examinations. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Separate original open-label and review limitations from direct details.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What was the actual scope of open-label design and central blinded review?
Application exceptions: Do not expand the absence of uniform central blinded review into an absence of all adjudication or examinations.
Referenced methods: M08 Table 8.2.a, M03 §3.2.4; our own application / M08 §8.1–8.2.3; our own application

Related sources R01

N15 · What is known about randomization, allocation concealment and baseline balance?

Current findings: The original summary describes DAHANCA as a multicenter randomized phase 3 trial. Actual tables or methods for sequence generation, concealment, stratification, baseline and cancer-treatment balance are absent.
Verification status: Unverified
Materials actually read: Summary read; external materials not read
Why unverified: Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Direct methods for allocation, concealment and baseline balance remain unverified.
Reason for missing information: Direct methods for allocation, concealment and baseline balance remain unverified.
Required materials and conditions: Allocation procedures, concealment, baseline and stratification factors and treatment balance
Materials to obtain first: Allocation procedures, concealment, baseline and stratification factors and treatment balance
Further research: Proposal: If original methods and baseline data are supplied, distinguish design labels from actual procedures.
Remaining uncertainty: Do not certify fulfillment of all methodological conditions from the randomized label, B2 or a past verdict. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Separate original design from gaps in direct procedures.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is known about randomization, allocation concealment and baseline balance?
Application exceptions: Do not certify fulfillment of all methodological conditions from the randomized label, B2 or a past verdict.
Referenced methods: M08 §8.1–8.2.3; our own application / M03 §3.2.1; detailed population conditions are our own design

Related sources R01

N16 · What does early stopping at the planned interim analysis preserve?

Current findings: The original trial account states that inferiority of the experimental arm at a planned interim analysis led to stopping at 522, before the planned 600.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Interim thresholds, boundaries, multiplicity, committee and subsequent follow-up details remain unverified.
Reason for missing information: Interim thresholds, boundaries, multiplicity, committee and subsequent follow-up details remain unverified.
Required materials and conditions: Interim timing and thresholds, committee, alpha, stopping and subsequent follow-up
Materials to obtain first: Interim timing and thresholds, committee, alpha, stopping and subsequent follow-up
Further research: Proposal: If original plans and stopping records are supplied, record prior rules and actual stopping and follow-up.
Remaining uncertainty: Do not turn the original planned-analysis wording into direct certification of advance planning or an exact bias magnitude. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Preserve the original stopping event and direct gaps in planning and follow-up.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What does early stopping at the planned interim analysis preserve?
Application exceptions: Do not turn the original planned-analysis wording into direct certification of advance planning or an exact bias magnitude.
Referenced methods: M08 Table 8.2.a, M04 §4.6.3; our own application / M08 §8.2.2, M15 §15.3.1; our own application / M15 §15.3.1–15.3.3; our own application

Related sources R01

N17 · Does hematologic correction constitute a tumor-control benefit?

Current findings: The original crux states that anemia measures improved but cancer control and survival worsened. Actual Hb changes, responders and target attainment are absent from the summary.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Quantitative Hb response, tumor oxygenation and mediation analyses remain unverified.
Reason for missing information: Quantitative Hb response, tumor oxygenation and mediation analyses remain unverified.
Required materials and conditions: Hematologic response, achieved Hb, denominator, tumor oxygenation and direct events
Materials to obtain first: Hematologic response, achieved Hb, denominator, tumor oxygenation and direct events
Further research: Proposal: If original response data are supplied, record Hb measures and clinical outcomes separately.
Remaining uncertainty: Do not treat increased Hb as a guarantee of oxygenation, tumor-control or survival improvement. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Preserve original hematologic statements separately from direct clinical worsening.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Does hematologic correction constitute a tumor-control benefit?
Application exceptions: Do not treat increased Hb as a guarantee of oxygenation, tumor-control or survival improvement.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M03 §3.2.4; our own extension boundary

Related sources R01

N18 · What is the original event-free-survival value?

Current findings: DAHANCA event-free survival HR 1.36 (1.09–1.69) is described in the original harmful direction. This is a different outcome from the locoregional-failure HR.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. EFS components, model, denominator and detailed interval confidence level remain unverified.
Reason for missing information: EFS components, model, denominator and detailed interval confidence level remain unverified.
Required materials and conditions: EFS definition and components, denominator, HR model and interval confidence level
Materials to obtain first: EFS definition and components, denominator, HR model and interval confidence level
Further research: Proposal: If original results and methods are supplied, link EFS components and estimand to that value.
Remaining uncertainty: Do not automatically copy locoregional-failure values or its 95% CI designation into EFS. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Keep the original EFS HR, interval and direction separate.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is the original event-free-survival value?
Application exceptions: Do not automatically copy locoregional-failure values or its 95% CI designation into EFS.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M03 §3.2.4; our own extension boundary

Related sources R01

N19 · What is the disease-specific-death result?

Current findings: DAHANCA disease-specific-death HR 1.43 (1.08–1.90) points in the original harmful direction. It is separate from overall death and failure.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Cause-of-death adjudication, events, risk population and detailed interval confidence level remain unverified.
Reason for missing information: Cause-of-death adjudication, events, risk population and detailed interval confidence level remain unverified.
Required materials and conditions: Cause-of-death adjudication, events and time, denominator, model and interval
Materials to obtain first: Cause-of-death adjudication, events and time, denominator, model and interval
Further research: Proposal: If original mortality outcomes are supplied, record causes, denominators and estimates separately.
Remaining uncertainty: Do not fill disease-specific death with another endpoint's HR or 95% designation. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Separate the original disease-specific HR from gaps in direct definitions.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is the disease-specific-death result?
Application exceptions: Do not fill disease-specific death with another endpoint's HR or 95% designation.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M03 §3.2.4; our own extension boundary

Related sources R01

N20 · What is the original overall-death HR?

Current findings: DAHANCA overall-death HR 1.30 (1.02–1.64) is described in the original harmful direction. It is not mixed with numbers from other survival or failure outcomes.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Original overall-death count, risk population and detailed interval confidence level remain unverified.
Reason for missing information: Original overall-death count, risk population and detailed interval confidence level remain unverified.
Required materials and conditions: Overall death, risk population and denominator, time, model and interval
Materials to obtain first: Overall death, risk population and denominator, time, model and interval
Further research: Proposal: If original mortality tables are supplied, record the actual overall-death estimate, time and denominator.
Remaining uncertainty: Do not calculate death counts, absolute-risk differences or new intervals from the original HR. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Preserve original overall-death values and gaps.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is the original overall-death HR?
Application exceptions: Do not calculate death counts, absolute-risk differences or new intervals from the original HR.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M03 §3.2.4; our own extension boundary

Related sources R01

N21 · Is the sibling survival-improvement question separate from the main tumor question?

Current findings: The sibling survival question is improved survival, grade F, with a note about harmful disease-specific and overall death. It is preserved as context and remains separate from the selected locoregional question.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. This record also contains no distinct score, status or axes for the sibling.
Reason for missing information: This record also contains no distinct score, status or axes for the sibling.
Required materials and conditions: Existing sibling question, endpoint definitions and denominators and original-result links
Materials to obtain first: Existing sibling question, endpoint definitions and denominators and original-result links
Further research: Proposal: If the original question changes, separately record each existing question and its links.
Remaining uncertainty: Do not count the sibling row as a new trial or participant group or copy failure values into survival outcomes. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Distinguish original survival context from the selected question.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Is the sibling survival-improvement question separate from the main tumor question?
Application exceptions: Do not count the sibling row as a new trial or participant group or copy failure values into survival outcomes.
Referenced methods: M03 §3.1, §3.2.1–3.2.4 question-clarification principles; detailed separation rules are our own design / M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M03 §3.2.4; our own extension boundary

Related sources R01

N22 · What are the details of follow-up, treatment deviations, missingness and censoring?

Current findings: Evaluable 513, five-year cumulative results and early stopping are preserved. Individual follow-up, treatment deviation or crossover, exclusions, censoring and ITT/PP details are absent from the summary.
Verification status: Unverified
Materials actually read: Summary read; external materials not read
Why unverified: Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Individual follow-up and deviations, ITT/PP and censoring and missing-data handling details remain unverified.
Reason for missing information: Individual follow-up and deviations, ITT/PP and censoring and missing-data handling details remain unverified.
Required materials and conditions: Endpoint-specific flow, follow-up and censoring, treatment deviations and missing-data handling
Materials to obtain first: Endpoint-specific flow, follow-up and censoring, treatment deviations and missing-data handling
Further research: Proposal: If original flow and analyses are supplied, distinguish allocation, evaluation, risk populations and losses.
Remaining uncertainty: Do not calculate or infer new attrition or analysis rules from differences in allocation and evaluation counts. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Record direct gaps in original flow and time.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are the details of follow-up, treatment deviations, missingness and censoring?
Application exceptions: Do not calculate or infer new attrition or analysis rules from differences in allocation and evaluation counts.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design / M08 §8.2.2, M15 §15.3.1; our own application / M19 §19.1.2–19.2.4, M04 §4.6.3; our own application

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N23 · What history underlies the original registration-absence statements?

Current findings: The original DAHANCA and ENHANCE registration values say absent because they predate registration requirements; RTOG records NCT00004917, and the review says not applicable. These original expressions are preserved; external registration existence was not currently verified.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. External registration existence and prior plans remain unread.
Reason for missing information: External registration existence and prior plans remain unread.
Required materials and conditions: Original registration, timing, contemporaneous records and plans and changes
Materials to obtain first: Original registration, timing, contemporaneous records and plans and changes
Further research: Proposal: If original registration and planning materials are supplied, distinguish actual existence and contents from original history.
Remaining uncertainty: Do not turn the historical absence wording into current certification of exhaustive registry absence or a new identifier. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Distinguish original values from the current unqueried scope.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What history underlies the original registration-absence statements?
Application exceptions: Do not turn the historical absence wording into current certification of exhaustive registry absence or a new identifier.
Referenced methods: M04 §4.5–4.6 material-collection and selection principles; separation of access and reading and hyperlink rules are our own design / M04 §4.5, §4.6.3; current material-conversion limits reflect review scope and our own design / M08 Table 8.2.a, M04 §4.6.3; our own application

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N24 · Were prior endpoints, interim plans and the hierarchy of multiple outcomes read?

Current findings: The original account includes primary failure, a planned interim analysis and major survival outcomes. Protocols, SAPs, all secondary and exploratory hierarchies, multiplicity and changes remain unread.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Direct documents for prior hierarchies, testing and changes remain unverified.
Reason for missing information: Direct documents for prior hierarchies, testing and changes remain unverified.
Required materials and conditions: Original plans, prior hierarchy, interim and final testing and changes
Materials to obtain first: Original plans, prior hierarchy, interim and final testing and changes
Further research: Proposal: If original plans are supplied, distinguish contemporaneous roles from reports and follow-up.
Remaining uncertainty: Do not certify every prior definition solely from the original primary-endpoint or planned-analysis labels. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Separate original roles from gaps in planning details.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Were prior endpoints, interim plans and the hierarchy of multiple outcomes read?
Application exceptions: Do not certify every prior definition solely from the original primary-endpoint or planned-analysis labels.
Referenced methods: M08 Table 8.2.a, M04 §4.6.3; our own application / M04 §4.5–4.6 material-collection and selection principles; separation of access and reading and hyperlink rules are our own design

Related sources R01

N25 · What are the clinical thresholds, individual effects and subgroups?

Current findings: Original failure and HR intervals and harmful-survival statements are available. Clinical-success thresholds, individual-response criteria and Hb, stage or population interactions are absent from the summary.
Verification status: Unverified
Materials actually read: Summary read; external materials not read
Why unverified: Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Prior clinical thresholds and direct subgroup effects and denominators remain unverified.
Reason for missing information: Prior clinical thresholds and direct subgroup effects and denominators remain unverified.
Required materials and conditions: Prior importance thresholds and subgroup hypotheses, interactions, denominators and intervals
Materials to obtain first: Prior importance thresholds and subgroup hypotheses, interactions, denominators and intervals
Further research: Proposal: If original plans or subgroup data are supplied, distinguish overall estimates from separate conditions.
Remaining uncertainty: Do not copy original effects into every stage, Hb target, dose or individual outcome. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Record overall original results and gaps in subgroup effects and clinical importance.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are the clinical thresholds, individual effects and subgroups?
Application exceptions: Do not copy original effects into every stage, Hb target, dose or individual outcome.
Referenced methods: M15 §15.3.1–15.3.3; our own application / M03 §3.2.1–3.2.4; dose, persistence and effect-modification details are our own design

Related sources R01

N26 · What are ENHANCE's original population, design and RR results?

Current findings: The original ENHANCE notation is 351 patients (epoetin beta 180, placebo 171), ITT. Primary locoregional progression-free survival adjusted RR 1.62 (95% CI 1.22–2.14), P=.0008, and survival RR 1.39 (1.05–1.84) point in the original harmful direction.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Adjustment variables, actual endpoints and ITT handling and detailed survival-interval confidence level remain unverified.
Reason for missing information: Adjustment variables, actual endpoints and ITT handling and detailed survival-interval confidence level remain unverified.
Required materials and conditions: PFS and survival definitions, adjusted model, actual denominators, ITT and intervals
Materials to obtain first: PFS and survival definitions, adjusted model, actual denominators, ITT and intervals
Further research: Proposal: If original ENHANCE methods and tables are supplied, record RR notation, estimand and endpoint-specific analyses.
Remaining uncertainty: Do not change original RRs into DAHANCA HRs or probabilities of improvement. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Preserve each original RR, interval and P value and trial-specific denominator and hierarchy.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are ENHANCE's original population, design and RR results?
Application exceptions: Do not change original RRs into DAHANCA HRs or probabilities of improvement.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M08 §8.1–8.2.3; our own application

Related sources R02

N27 · How do epoetin beta, epoetin alfa and darbepoetin exposures differ?

Current findings: The original verdict concerns three ESAs in the same head-and-neck radiotherapy setting, rather than one drug alone. Trial-specific doses, Hb targets, actual exposures and combinations are not detailed in the summary.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Direct details of trial-specific targets, exposures, combinations and actual Hb remain unverified.
Reason for missing information: Direct details of trial-specific targets, exposures, combinations and actual Hb remain unverified.
Required materials and conditions: Drug-specific formulation, amount and targets, shared and different treatments and populations
Materials to obtain first: Drug-specific formulation, amount and targets, shared and different treatments and populations
Further research: Proposal: If original intervention data are supplied, record drugs, targets and trial-specific conditions separately.
Remaining uncertainty: Do not fill different drugs or targets with the same dose or conditions or extend them to every other indication. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Record shared claim context together with actual drug and exposure differences.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: How do epoetin beta, epoetin alfa and darbepoetin exposures differ?
Application exceptions: Do not fill different drugs or targets with the same dose or conditions or extend them to every other indication.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and assessment adaptations are our own design / M03 §3.2.3, M08 §8.2.2–8.2.3; our own application / M03 §3.2.1–3.2.4; dose, persistence and effect-modification details are our own design

Related sources R01 R02 R03

N28 · What are RTOG's initial and long-term endpoint values?

Current findings: RTOG's 148 patients are described as showing no epoetin alfa benefit. Three-year failure 44% versus 36% (P=.56), five-year failure 46.2% versus 39.4% (P=.42) and OS 36.9% versus 38.2% (P=.54) are separately preserved.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Actual analysis denominators, original CIs and models and detailed OS timepoint definitions remain unverified.
Reason for missing information: Actual analysis denominators, original CIs and models and detailed OS timepoint definitions remain unverified.
Required materials and conditions: Timepoint-specific failure and OS, denominators, estimates, CIs and analysis plans
Materials to obtain first: Timepoint-specific failure and OS, denominators, estimates, CIs and analysis plans
Further research: Proposal: If original RTOG tables are supplied, link each timepoint and endpoint to its original intervals and denominators.
Remaining uncertainty: Do not turn nonsignificance into zero effect, equivalence or guaranteed individual survival. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Keep original timepoints, proportions and P values attached to their respective endpoints.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are RTOG's initial and long-term endpoint values?
Application exceptions: Do not turn nonsignificance into zero effect, equivalence or guaranteed individual survival.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design

Related sources R03

N29 · Do the two RTOG PMIDs refer to reports of the same trial?

Current findings: The RTOG citation preserves initial PMID 17716826 and long-term PMID 25670542 together. Its original flag groups reports of the same trial as one. The URL identifies the long-term report's bibliography.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Actual follow-up and denominators of the follow-up report and each original full text remain unread.
Reason for missing information: Actual follow-up and denominators of the follow-up report and each original full text remain unread.
Required materials and conditions: Initial and follow-up populations, timepoints and analysis and report relationships
Materials to obtain first: Initial and follow-up populations, timepoints and analysis and report relationships
Further research: Proposal: If original reports are supplied, distinguish same-cohort follow-up from separate trials.
Remaining uncertainty: Do not add two PMIDs or timepoints as two groups of 148 participants or independent replications. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Preserve the original report group, bibliography and same-population relationship.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Do the two RTOG PMIDs refer to reports of the same trial?
Application exceptions: Do not add two PMIDs or timepoints as two groups of 148 participants or independent replications.
Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort and outcome linking is our own application / M04 §4.6.1–4.6.2, M15 §15.3.1; our own application

Related sources R03

N30 · Can the five-RCT, 1,397-participant review be added to original trials?

Current findings: The original review size is five RCTs and 1,397 participants. Report and included-trial lists and overlap with current original trials and follow-up were not directly read.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Review inclusion, contributions and unique trial and participant totals remain undetermined.
Reason for missing information: Review inclusion, contributions and unique trial and participant totals remain undetermined.
Required materials and conditions: Inclusion and contribution lists, trial identities, populations and timepoints and overlap
Materials to obtain first: Inclusion and contribution lists, trial identities, populations and timepoints and overlap
Further research: Proposal: If original inclusion tables are supplied, link the review to unique original study families.
Remaining uncertainty: Do not add review 1,397 and individual trials or follow-up to create new participant or trial totals. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Distinguish original review counts from undetermined unique totals.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Can the five-RCT, 1,397-participant review be added to original trials?
Application exceptions: Do not add review 1,397 and individual trials or follow-up to create new participant or trial totals.
Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort and outcome linking is our own application / M04 §4.6.1–4.6.2, M15 §15.3.1; our own application / M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design

Related sources R04

N31 · What is the event direction of the review's ORs?

Current findings: OS Peto OR 0.73 (95% CI 0.58–0.91) and locoregional PFS OR 0.63 (0.49–0.80) are originally described as worse with radiotherapy plus EPO and favoring radiotherapy alone.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. OR coding, synthesis model and detailed PFS-interval confidence level remain unverified.
Reason for missing information: OR coding, synthesis model and detailed PFS-interval confidence level remain unverified.
Required materials and conditions: Review event and success coding, models and endpoint-specific contributions and intervals
Materials to obtain first: Review event and success coding, models and endpoint-specific contributions and intervals
Further research: Proposal: If original review tables are supplied, record OR coding, estimands and contributions.
Remaining uncertainty: Do not reverse OR<1 into reduced death or failure with ESA or convert it into an HR or RR. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Preserve the original review direction, measures and intervals at their stated level.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is the event direction of the review's ORs?
Application exceptions: Do not reverse OR<1 into reduced death or failure with ESA or convert it into an HR or RR.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are our own design / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design / M15 §15.3.1–15.3.3; our own application

Related sources R04

N32 · What are the review's timing, subsets, heterogeneity and direct comparisons?

Current findings: The review's original bibliography is from 2009, whereas the original DAHANCA report is from 2018. Actual inclusion and updates, contributions by drug, target and timepoint, heterogeneity and subgroup analyses are absent from the summary.
Verification status: Unverified
Materials actually read: Summary read; external materials not read
Why unverified: Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Temporal relationships between versions and inclusion, subsets and quantitative heterogeneity remain unverified.
Reason for missing information: Temporal relationships between versions and inclusion, subsets and quantitative heterogeneity remain unverified.
Required materials and conditions: Review version, inclusion timing, endpoint subsets, synthesis, heterogeneity and conditions
Materials to obtain first: Review version, inclusion timing, endpoint subsets, synthesis, heterogeneity and conditions
Further research: Proposal: If original review tables are supplied, record versions and actual included families and conditions.
Remaining uncertainty: Do not assume every recent report was included in the review or arbitrarily correct years or identities. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Preserve original dates and bibliography and gaps in actual inclusion.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are the review's timing, subsets, heterogeneity and direct comparisons?
Application exceptions: Do not assume every recent report was included in the review or arbitrarily correct years or identities.
Referenced methods: M04 §4.6.1–4.6.2, M15 §15.3.1; our own application / M08 §8.2.2, M15 §15.3.1; our own application / M03 §3.2.1–3.2.4; dose, persistence and effect-modification details are our own design

Related sources R04

N33 · Are repeated refutation in the same indication and other goals distinguished?

Current findings: The original scope is limited to improved tumor control during cancer radiotherapy. Kidney-disease anemia and transfusion reduction in very-low-birth-weight preterm infants, verdict 2925 B72, concern different populations and goals.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Pages and original materials for other indications remain unread.
Reason for missing information: Pages and original materials for other indications remain unread.
Required materials and conditions: Direct questions, exposures and endpoints for each indication and goal
Materials to obtain first: Direct questions, exposures and endpoints for each indication and goal
Further research: Proposal: If materials for another requested question are supplied, record its original unit and population separately.
Remaining uncertainty: Do not merge 2925 as tumor-control benefit, safety evidence or a separate anticancer trial here. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Preserve only the original link context for another goal and do not create treatment-selection instructions.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are repeated refutation in the same indication and other goals distinguished?
Application exceptions: Do not merge 2925 as tumor-control benefit, safety evidence or a separate anticancer trial here.
Referenced methods: M03 §3.2.1; detailed population conditions are our own design / M03 §3.2.2–3.2.3; reverse-direction labeling and assessment adaptations are our own design / M03 §3.2.4; our own extension boundary

Related sources R01 R02 R03 R04

N34 · What is the original statement of no differences in ancillary safety?

Current findings: The original counterview says no excess serious adverse events, cardiovascular increase or differences in acute or late radiation toxicity were identified. Quantitative events, denominators, CIs and P values are absent from the summary.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Direct safety event counts, intervals and collection methods remain unverified.
Reason for missing information: Direct safety event counts, intervals and collection methods remain unverified.
Required materials and conditions: Safety definitions and collection, individual events and denominators, estimates and intervals
Materials to obtain first: Safety definitions and collection, individual events and denominators, estimates and intervals
Further research: Proposal: If original safety tables are supplied, record original observations and intervals for each item.
Remaining uncertainty: Do not turn unverified differences into zero events, equivalence of all safety outcomes or harmlessness. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Preserve both original ancillary-safety statements and direct clinical worsening.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is the original statement of no differences in ancillary safety?
Application exceptions: Do not turn unverified differences into zero events, equivalence of all safety outcomes or harmlessness.
Referenced methods: M19 §19.1.2–19.2.4; detailed distinctions are our own design / M19 §19.2.2–19.2.4, M03 §3.2.3; our own application / M19 §19.1.2–19.2.4; our own application / M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is our own design

Related sources R01

N35 · Are major tumor and survival harms separate from safety collection?

Current findings: The original explanation states that demonstrated harm came from primary and major tumor-control and survival endpoints, rather than ancillary safety items. A complete list of all adverse events is absent from the summary.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Complete harm definitions, collection, discontinuation and severity tables remain unverified.
Reason for missing information: Complete harm definitions, collection, discontinuation and severity tables remain unverified.
Required materials and conditions: Clinical-harm and safety endpoints, collection and adjudication, severity and discontinuation
Materials to obtain first: Clinical-harm and safety endpoints, collection and adjudication, severity and discontinuation
Further research: Proposal: If original safety and endpoint data are supplied, distinguish actual clinical outcomes from separate collection.
Remaining uncertainty: Do not erase demonstrated tumor or survival harm based on no differences in ancillary safety. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Distinguish endpoint-specific harm from gaps in complete collection.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are major tumor and survival harms separate from safety collection?
Application exceptions: Do not erase demonstrated tumor or survival harm based on no differences in ancillary safety.
Referenced methods: M19 §19.1.2–19.2.4; detailed distinctions are our own design / CHAMGAP's own interpretation boundary. M19 principles are referenced; no official causality tool was run / M19 §19.1.2–19.2.4; our own application

Related sources R01

N36 · What are harm-event, participant and time denominators and timepoints?

Current findings: Original context includes evaluable 513, five-year tumor outcomes and interim stopping. Numbers and time at risk for each safety event, onset, recovery, exposure and discontinuation timing are absent.
Verification status: Unverified
Materials actually read: Summary read; external materials not read
Why unverified: Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Denominators, time, discontinuation and recovery for each safety event remain unverified.
Reason for missing information: Denominators, time, discontinuation and recovery for each safety event remain unverified.
Required materials and conditions: Safety-specific denominators and durations, event timing and treatment and follow-up discontinuation
Materials to obtain first: Safety-specific denominators and durations, event timing and treatment and follow-up discontinuation
Further research: Proposal: If original safety flow is supplied, record efficacy evaluation separately from safety exposure and time.
Remaining uncertainty: Do not copy 513/522 or five-year figures as actual denominators or duration for every harm. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Separate original clinical context from gaps in safety time and denominators.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are harm-event, participant and time denominators and timepoints?
Application exceptions: Do not copy 513/522 or five-year figures as actual denominators or duration for every harm.
Referenced methods: M19 §19.2 design-specific harm questions; temporal-relationship details are our own design / M19 §19.1.2–19.2.4; our own application / M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are our own design

Related sources R01

N37 · What is known about baseline cancer risk, concurrent treatments and alternative attribution?

Current findings: Radiotherapy and ESA comparisons and clinical worsening are original-summary observations. Actual event-specific details of baseline and concurrent treatments, disease characteristics, other exposures and adjustment are absent.
Verification status: Unverified
Materials actually read: Summary read; external materials not read
Why unverified: Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Individual-event alternatives, mechanisms, concurrent treatments and adjustment details remain unverified.
Reason for missing information: Individual-event alternatives, mechanisms, concurrent treatments and adjustment details remain unverified.
Required materials and conditions: Baseline and concurrent exposures, event attribution, adjustment and alternative explanations
Materials to obtain first: Baseline and concurrent exposures, event attribution, adjustment and alternative explanations
Further research: Proposal: If original methods and event data are supplied, distinguish randomized comparisons from individual causes and mechanisms.
Remaining uncertainty: Do not turn population-level harmful direction into established causes or mechanisms for individual patients. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Separate original comparisons from gaps in attribution and mechanisms.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is known about baseline cancer risk, concurrent treatments and alternative attribution?
Application exceptions: Do not turn population-level harmful direction into established causes or mechanisms for individual patients.
Referenced methods: M19 §19.2.2–19.2.4 design considerations; detailed confounding records are our own design / M03 §3.2.3, M08 §8.2.2–8.2.3; our own application

Related sources R01

N38 · What is known about missing and complete safety and clinical follow-up?

Current findings: Original history includes evaluation and allocation, early stopping and open-label design. Safety surveillance, follow-up losses, omissions, censoring and completeness of all event reporting are absent from the summary.
Verification status: Unverified
Materials actually read: Summary read; external materials not read
Why unverified: Required direct details are absent from the preserved summary and remain unverified. External materials remain unread. Safety follow-up, omissions and overall reporting completeness remain unverified.
Reason for missing information: Safety follow-up, omissions and overall reporting completeness remain unverified.
Required materials and conditions: Safety and clinical flow, losses and omissions, reporting and censoring and sensitivity
Materials to obtain first: Safety and clinical flow, losses and omissions, reporting and censoring and sensitivity
Further research: Proposal: If original flow and surveillance records are supplied, distinguish observed outcomes from uncaptured and missing data.
Remaining uncertainty: Do not turn allocation and evaluation differences into absence of safety events or an exact bias magnitude. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Record original outcome limitations in follow-up and reporting.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is known about missing and complete safety and clinical follow-up?
Application exceptions: Do not turn allocation and evaluation differences into absence of safety events or an exact bias magnitude.
Referenced methods: M19 §19.1.2–19.2.4, M04 §4.6.3; our own application / M08 §8.2.2, M15 §15.3.1; our own application

Related sources R01

N39 · What is the scope of FDA warnings, original harm, current verification and causality?

Current findings: Original advertising interpretation and safety explanation preserve the FDA boxed warning about shortened cancer survival and tumor progression or recurrence. The preserved summary contains no regulatory-original URL or separate citation. Current approvals and warning contents were not queried.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Official warning and approval texts, latest versions and direct mechanistic verification remain unread.
Reason for missing information: Official warning and approval texts, latest versions and direct mechanistic verification remain unread.
Required materials and conditions: Original regulatory text and versions, indications and clinical-outcome and judgment scope
Materials to obtain first: Original regulatory text and versions, indications and clinical-outcome and judgment scope
Further research: Proposal: If original regulatory materials are supplied, distinguish historical statements from direct contents and current updates.
Remaining uncertainty: Do not create new regulatory links, certify current approval or provide treatment, medication, radiotherapy-selection or dosing instructions. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Separate original warnings and clinical harm from the current unqueried regulatory scope.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What is the scope of FDA warnings, original harm, current verification and causality?
Application exceptions: Do not create new regulatory links, certify current approval or provide treatment, medication, radiotherapy-selection or dosing instructions.
Referenced methods: CHAMGAP's own interpretation boundary. M19 principles are referenced; no official causality tool was run / M04 §4.5–4.6 material-collection and selection principles; separation of access and reading and hyperlink rules are our own design / M04 §4.5, §4.6.3; current material-conversion limits reflect review scope and our own design

Related sources R01

N40 · Does this answer questions about other cancers, Hb targets, populations or long-term and rare harms?

Current findings: The original verdict concerns tumor control during head-and-neck radiotherapy. Direct results for other cancers, populations, Hb targets, other ESA exposures or rare and other long-term harms are absent from this summary.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Direct evidence for other populations, goals and rare harms remains unverified.
Reason for missing information: Direct evidence for other populations, goals and rare harms remains unverified.
Required materials and conditions: Direct population-, target- and exposure-specific materials and safety follow-up
Materials to obtain first: Direct population-, target- and exposure-specific materials and safety follow-up
Further research: Proposal: If direct materials are supplied, distinguish the selected claim from other indication and harm questions.
Remaining uncertainty: Do not extend original repeated refutation to identical harm for every ESA indication and exposure. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Record original limits and gaps in safety and effect extensions.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Does this answer questions about other cancers, Hb targets, populations or long-term and rare harms?
Application exceptions: Do not extend original repeated refutation to identical harm for every ESA indication and exposure.
Referenced methods: M19 §19.1.2–19.2.4; our own application / M03 §3.2.1–3.2.4; dose, persistence and effect-modification details are our own design / M03 §3.2.1; detailed population conditions are our own design

Related sources R01

N41 · What were DAHANCA's mixed support, device or drug supply and roles?

Current findings: Danish Cancer Society and Amgen support, Amgen's free trial drug/Aranesp and main GCP and quality-control costs are preserved. The original account says the trial was investigator driven, Amgen had no design, conduct, collection or analysis role and offered no comments despite a manuscript-comment opportunity.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Original contracts, complete declarations and direct current role comparisons remain unread.
Reason for missing information: Original contracts, complete declarations and direct current role comparisons remain unread.
Required materials and conditions: Original sponsorship and supply, roles, contracts and data access and COI declarations
Materials to obtain first: Original sponsorship and supply, roles, contracts and data access and COI declarations
Further research: Proposal: If original declarations are supplied, distinguish support and supply from each actual operational role.
Remaining uncertainty: Do not remove free-drug/GCP-cost or noninvolvement statements or upgrade I1 to current independence certification. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Separate original support, supply and role context from currently unread declarations.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What were DAHANCA's mixed support, device or drug supply and roles?
Application exceptions: Do not remove free-drug/GCP-cost or noninvolvement statements or upgrade I1 to current independence certification.
Referenced methods: CHAMGAP's own independence and attribution conditions. Official methodological sections used in this pilot do not guarantee every detail of this item / M04 §4.6.1–4.6.2, M15 §15.3.1; our own application

Related sources R01

N42 · What are funding and author relationships in other trials and the review?

Current findings: Original accounts record F. Hoffmann-La Roche support for ENHANCE, NCI/Ortho Biotech support for RTOG and mixed public and company funding of the review's included trials. Detailed company and investigator roles and the review's own declarations are absent.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Detailed roles, the review's own funding and COIs and investigator and population overlap remain unverified.
Reason for missing information: Detailed roles, the review's own funding and COIs and investigator and population overlap remain unverified.
Required materials and conditions: Report-specific sponsorship and supply, author, analysis and manuscript roles and review declarations
Materials to obtain first: Report-specific sponsorship and supply, author, analysis and manuscript roles and review declarations
Further research: Proposal: If original declarations and inclusion tables are supplied, record roles, families and funding by report.
Remaining uncertainty: Do not certify current investigator or population independence solely from different supporting institutions. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Preserve report-specific original funding and relationship gaps.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: What are funding and author relationships in other trials and the review?
Application exceptions: Do not certify current investigator or population independence solely from different supporting institutions.
Referenced methods: CHAMGAP's own independence and attribution conditions. Official methodological sections used in this pilot do not guarantee every detail of this item / M04 §4.6.1–4.6.2 distinction between studies and reports; cohort and outcome linking is our own application

Related sources R02 R03 R04

N43 · Are original repeated refutation and unique trial and repeated-harm counts established?

Current findings: The original parent describes repeated refutation/RX across three different drugs and independent trials. This is preserved, but review inclusion, trial identities, replications and follow-up were not exhaustively compared, so unique counts and independence are not certified.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Unique trial totals, participant and event sums and independent repeated-harm counts remain undetermined.
Reason for missing information: Unique trial totals, participant and event sums and independent repeated-harm counts remain undetermined.
Required materials and conditions: Unique families, inclusion and follow-up, investigators and funding and event and population lists
Materials to obtain first: Unique families, inclusion and follow-up, investigators and funding and event and population lists
Further research: Proposal: If original lists are supplied, link same, different and uncertain families and repeated citations.
Remaining uncertainty: Do not add review, follow-up, the same population or endpoints as new independent trials or repeated events. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Distinguish original history from unrecorded, undetermined unique counts.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are original repeated refutation and unique trial and repeated-harm counts established?
Application exceptions: Do not add review, follow-up, the same population or endpoints as new independent trials or repeated events.
Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort and outcome linking is our own application / M04 §4.6.1–4.6.2, M15 §15.3.1; our own application / M04 §4.6.1–4.6.2; harm-material adaptations are our own design

Related sources R01 R02 R03 R04

N44 · Are original dates, corrections, Korean and English texts and empty values preserved?

Current findings: Date 2026-08-26, empty corrections and deliberation, Korean and English texts and parent-axis true, false, unrecorded and empty-string values are preserved.
Verification status: Partly verified
Materials actually read: Summary read; external materials not read
Why unverified: Original preserved-summary statements were linked for production as partly verified; clinical verification and content review are not complete. Separate evidence-cutoff and facet fields are absent; no latest correction, retraction or regulatory search was performed.
Reason for missing information: Separate evidence-cutoff and facet fields are absent; no latest correction, retraction or regulatory search was performed.
Required materials and conditions: Original dates, corrections and languages and current input and update scope
Materials to obtain first: Original dates, corrections and languages and current input and update scope
Further research: Proposal: If actual update materials are supplied, distinguish the complete original version from the correction event.
Remaining uncertainty: Do not borrow historical dates or cross-checking as current clinical-verification dates or certify exhaustive absence from empty corrections. Existing content review remains incomplete and external original materials were not directly verified.
Conditions for verification: Record original history together with current production and incomplete content review.
Why this condition is needed: This condition is needed to record original information and gaps separately for the question: Are original dates, corrections, Korean and English texts and empty values preserved?
Application exceptions: Do not borrow historical dates or cross-checking as current clinical-verification dates or certify exhaustive absence from empty corrections.
Referenced methods: M04 §4.5, §4.6.3; current material-conversion limits reflect review scope and our own design / M03 §3.1, §3.2.1–3.2.4 question-clarification principles; detailed separation rules are our own design

Related sources R01 R02 R03 R04