{ "schema_version": "chamgap-public-criteria-1.0", "title": "Oral cyanocobalamin ampule regimen × Day-90 hemoglobin in B12-deficiency megaloblastic anemia versus intramuscular administration of the same compound", "criteria_version": "NGM-v3113-CYANO-AMPULE-JUICE-IM-HB90-1.1", "criteria_date": "2026-10-05", "condition_origin": "Chamgap application criteria", "method_sources": [ { "id": "M03", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-03", "section": "§3.1, §3.2.1–3.2.3, MECIR C5/C7/C13", "official_principle": "Clearly record the question, eligibility criteria and reasons for changes, and distinguish variations in the intervention.", "review_level": "Reuse of the methodological principles/editions from 1585 and actual byte copies of 5 HTML files. Not new reading of full methodological texts or application of an official tool in this review" }, { "id": "M04", "version": "Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-04", "section": "§4.5, §4.6.1–4.6.3, MECIR C42", "official_principle": "Distinguish and link studies and reports, and do not omit a study solely because its outcomes are not reported.", "review_level": "Reuse of the methodological principles/editions from 1585 and actual byte copies of 5 HTML files. Not new reading of full methodological texts or application of an official tool in this review" }, { "id": "M08", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-08", "section": "§8.1–8.2.3, Table 8.2.a", "official_principle": "Hold the outcome and effect of interest fixed, then assess randomization, deviations, missing data, measurement and selective reporting.", "review_level": "Reuse of the methodological principles/editions from 1585 and actual byte copies of 5 HTML files. Not new reading of full methodological texts or application of an official tool in this review" }, { "id": "M15", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-15", "section": "§15.2.4, §15.3.1–15.3.3", "official_principle": "Distinguish effect estimates, intervals, importance and applicability. Sample size alone does not determine precision.", "review_level": "Reuse of the methodological principles/editions from 1585 and actual byte copies of 5 HTML files. Not new reading of full methodological texts or application of an official tool in this review" }, { "id": "M19", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-19", "section": "§19.1.2, §19.2.1–19.2.4", "official_principle": "Questions about harms may require designs, populations and follow-up different from efficacy questions. Case reports do not establish incidence.", "review_level": "Reuse of the methodological principles/editions from 1585 and actual byte copies of 5 HTML files. Not new reading of full methodological texts or application of an official tool in this review" } ], "status_dictionary": { "Partly verified": "Some actual retained information exists, but gaps remain in product/exposure/methods, original denominators/estimates/plans, harms/identity/original sources", "Unverified": "The required information/criterion cannot be established within this verification scope", "Review incomplete": "Original-material comparison/search was not performed within the authorized scope", "Not reported": "A scope-limited status indicating that the item was not stated in the specific material/section read", "Inaccessible": "Use only for material for which access was actually attempted and failed. Not assigned to the clinical materials in this review", "Insufficient eligible evidence": "Use only when, after reviewing relevant studies within the defined scope, evidence is insufficient to answer the criterion. Not applied across all items in this review", "Not applicable": "Extensions to optimal dosing, long-term outcomes, events or other products outside the selected day-90 Hb regimen comparison do not apply. Not a substitute for unverified actual inputs", "Conflicting information": "Use when materials that are difficult to reconcile for the same question, time point and analysis have been compared. Not assigned merely because review numbers differ", "Met": "Verification of the stated preservation, boundary, distinction or linkage criteria. Not new clinical efficacy verification, full-text reading or safety certification" }, "requirements": [ { "item_id": "N01", "question_type": "Independent claim", "question": "Which actual B12 regimens are being compared for day-90 Hb?", "needed": "The original question of day-90 Hb in adults with laboratory-confirmed B12-deficiency megaloblastic anemia: oral ampule+fruit juice versus the same compound IM", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid combining general B12 treatment, effects versus no treatment and all oral products into the same claim.", "application_exception": "Retain the original narrowed question and empty subclaims list; do not generate a separate combination of axes.", "criterion": "Link the original independent claim to the actual regimen, population, active comparator, endpoint and direction.", "basis": "M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Identify direct comparisons within this boundary, and treat other forms, populations and endpoints as separate questions." }, { "item_id": "N02", "question_type": "Chemical form and product", "question": "Is the cyanocobalamin product distinguished from unverified manufacturing details?", "needed": "Documentation of the original Dodex/Deva product's active ingredient, manufacturing origin, batch, purity, additional salt and release specifications", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid filling gaps in the original product's identity with data on other cobalamins and tablets.", "application_exception": "Do not transfer information on methyl/meco, hydroxo or adenosyl B12 or separately authorized products as if they were the same product.", "criterion": "Preserve the reported Dodex1000mcg cyanocobalamin and the unreported manufacturing/formulation details separately.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Compare the original trial product documentation and batch/ingredient records with actual administration records." }, { "item_id": "N03", "question_type": "Actual route and physical formulation", "question": "Is oral ampule+fruit juice being read as a tablet comparison or an isolated-route comparison?", "needed": "The original S01 section on oral ampule contents/20mL fruit juice, the same IM product and actual administration methods", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid changing the swallowing method and administration context into another product/route.", "application_exception": "This is the actual regimen including fruit juice; pharmacokinetic equivalence of the routes requires separate evidence.", "criterion": "Attribute the oral arm's ampule+fruit juice and nurse-administered IM to the actual comparison.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Check the original administration section and product records, and design an isolated-route/formulation comparison separately." }, { "item_id": "N04", "question_type": "Nominal dose and cumulative dose", "question": "Is the 1000mcg schedule distinguished from the exact 90-day total?", "needed": "Nominal dose for 1 time in each arm, daily/weekly/monthly schedules, administration dates throughout 90 days and actual total dose", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting the subtotal for the first 14 administrations into the full 90-day dose or a personal recommendation.", "application_exception": "Preserve the historical subtotal of 14000mcg unchanged; do not perform new conversions or calculations in this review.", "criterion": "Show 1000mcg daily for 10 days→1 time per week for 4 weeks→1 time per month separately from the unverified total dose.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Link original prescription/administration dates and actual doses taken in each arm to the time points and denominators." }, { "item_id": "N05", "question_type": "Actual adherence and concurrent exposure", "question": "Have actual doses taken and dietary/concurrent B12 been verified?", "needed": "Arm-specific adherence/missed administrations, diet, fortified foods, concurrent B12 and exposure records and analyses", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting planned administration into equal actual exposure or complete adherence.", "application_exception": "Do not infer 100% adherence or PP if quantitative adherence is not stated in the original source.", "criterion": "Keep nominal exposure separate from gaps in verification of actual adherence and concurrent exposure.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Compare arm-specific dosing/missed administrations and dietary/concurrent exposure with the effects of assignment/adherence." }, { "item_id": "N06", "question_type": "Observation period", "question": "Is 90-day observation separated from the lifelong monthly plan?", "needed": "Distinguishing S01 administration, visits/end of observation and monthly maintenance plans from actual follow-up", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid extending an administration plan to observation, efficacy or safety throughout that period.", "application_exception": "Do not require a lifelong efficacy trial for the selected 90-day question.", "criterion": "Record 90-day observation and the lifelong plan of 1 time per month separately.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "When asking about maintenance or effects after discontinuation, obtain actual long-term follow-up and its denominators separately." }, { "item_id": "N07", "question_type": "Actual population and cutoffs", "question": "Which adults with B12-deficiency anemia were compared?", "needed": "Inclusion/exclusion for ages 32–87, nonpregnant/nonlactating status, B12<160pg/mL, MCV>94fL, megaloblastic anemia and Hb<12 in the analyzed groups", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid applying the result to the general population with normal B12, children or pregnant/lactating groups.", "application_exception": "Do not generalize the laboratory cutpoints and Hb in the analyzed groups into criteria for all patients with anemia.", "criterion": "Describe the population actually reported and the question's boundaries, with each laboratory measure and unit.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Link original eligibility, baseline distributions and exclusions to the actual denominators of the direct comparison." }, { "item_id": "N08", "question_type": "Causes and iron/folate status", "question": "Is the entire cohort being called confirmed pernicious anemia, or are cause-specific Hb results being invented?", "needed": "Dietary/gastric, malabsorption and unverified causes; intrinsic-factor testing, iron/folate status and cause-specific Hb", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting mixed causes into a single confirmed diagnosis or a common effect across all causes.", "application_exception": "Do not convert the retained record that intrinsic-factor testing was not performed into absence of pernicious anemia.", "criterion": "Separate normal folate from unverified iron status and cause-specific Hb, and distinguish the mixed diagnoses.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Review causes/baseline tests and prespecified stratified Hb comparisons with the actual denominators." }, { "item_id": "N09", "question_type": "Comparator, concomitant treatment and rescue treatment", "question": "Can the same IM schedule be distinguished from common anemia treatment?", "needed": "Actual records of the same Dodex IM, arm-specific iron/folate/transfusion/EPO, rescue treatment/changes, adherence and fruit juice", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid attributing differences in concomitant treatment to the contribution of oral B12 itself.", "application_exception": "Do not write that common treatment was absent because it was not reported, or require all changes to be identical.", "criterion": "Distinguish the same active ingredient/nominal schedule from unverified concomitant treatment and actual exposure in each arm.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application; M19 §19.2.2–19.2.4 design considerations; detailed confounding records are internally designed", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Compare arm-specific background treatment, changes/rescue records and the analysis of the Hb effect of interest." }, { "item_id": "N10", "question_type": "Hb measurement", "question": "Is the objectivity of Hb the same as verification of actual testing and assessor blinding?", "needed": "Hb(g/dL) assay method/time points, measurements by arm, analyst blinding and missing measurements/errors", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid claiming that Hb measurement bias is resolved by the name of an objective test or by endoscopy blinding.", "application_exception": "Do not automatically convert unverified blinding into measurement error or trial failure.", "criterion": "Separate objective Hb from unverified assessor/arm-specific measurement conditions.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application; M03 §3.2.4; internally defined boundaries for extending the claim", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Compare the original assay section with Hb assessment/time points and denominators by arm." }, { "item_id": "N11", "question_type": "Endpoint and day-90 hierarchy", "question": "Is an article-stated primary Hb endpoint the same as a registry-verified unique primary visit?", "needed": "Original Response Criteria/table, CBC visit list and endpoint/time-point hierarchy in the registry/protocol/SAP", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting the article's last visit into the unique preregistered primary time point.", "application_exception": "Disclose the difference between the abbreviated CBC list and the day-90 table, but do not establish selective reporting on the basis of an unavailable plan.", "criterion": "Distinguish Hb as one of the primary endpoints and the final day-90 visit from the unverified registry hierarchy.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Compare the original plan/visit schedule and registry amendment history with the actually reported day-90 assessment." }, { "item_id": "N12", "question_type": "Arm-specific Hb and SD", "question": "Are arm-specific Hb means/SDs at baseline and day 90 linked without changing their values?", "needed": "Oral/IM baseline and day-90 means(SD), g/dL and analyzed denominators 26/34 in the original S01 table", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid confusing baseline with endpoint, SD with SE or between-group with within-group results, or converting rounded values into high-precision original values.", "application_exception": "The retained numbers are not the results of a current visual comparison with the original PDF or of new calculations.", "criterion": "Preserve the four arm-specific means/SDs with their correct time points, units and denominators.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "When checking the original table/transcription's numbers, definitions of dispersion and denominators at each time point, preserve and compare all before/after values." }, { "item_id": "N13", "question_type": "Unadjusted endpoint difference", "question": "For which between-group effect is +0.10g/dL the retained calculation?", "needed": "Direction and calculation provenance of the unadjusted day-90 endpoint mean difference, and absence of the prioritized adjusted/change effect", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting an editorial reconstruction into an originally reported adjusted effect or a registered analysis.", "application_exception": "Preserve the historical +0.10; do not perform a Mann–Whitney/NI analysis or recalculation in this review.", "criterion": "Explain its provenance as oral−IM, day-90 endpoint values, unadjusted, and a historical editorial substitute.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If the original adjusted/change estimand becomes available, compare its definition and values in a separate version." }, { "item_id": "N14", "question_type": "Within-group change and causality", "question": "Are +5.4 in both arms and a rounded change difference of 0 being read as no effect/equivalence?", "needed": "Rounded within-group changes, between-group effects, change variance/CI and definition of the comparison", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting improvement in both arms into efficacy versus no treatment or verified equivalence.", "application_exception": "The historical 5.4/5.4 and 0 are descriptive only; do not create a new test of the difference in changes.", "criterion": "Distinguish within-group changes and the rounded change difference from the active-comparator interpretation currently possible.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Check the original change-score variance/between-group CI and analysis, and review them separately from endpoint-value results." }, { "item_id": "N15", "question_type": "Adjusted and change estimates", "question": "Were the adjusted endpoint difference and change-score uncertainty reported?", "needed": "Baseline-adjusted endpoint effect/model, change SD/CI, analysis population and handling of missing data", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid arbitrarily calculating a change SD or adjusted effect from the endpoint SD.", "application_exception": "Do not expand an empty value into 0, equivalence or a statement that the item is unreported throughout the original article's full text.", "criterion": "Preserve the current empty values for the adjusted effect, change CI and exact between-group P, together with the original scope of access.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M15 §15.3.1–15.3.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Obtain the original analysis/supplement, arm-specific paired-change variance/covariance and handling of missing data." }, { "item_id": "N16", "question_type": "Reconstructed CI", "question": "Are the exact values, provenance and interpretive limitations of the 95% CI preserved?", "needed": "C02 editor-reconstructed endpoint-difference CI, original arm-specific SDs/denominators, calculation conditions and clinically important difference", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting a calculated interval into a CI reported in the original article or into exclusion of meaningful benefit.", "application_exception": "Preserve the historical exact values [-0.313492,0.513492] and display −0.31~+0.51; do not recalculate them in this review.", "criterion": "Explain the editor-reconstructed 95%CI, inclusion of 0/differences in both directions and the unverified important margin together.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M15 §15.3.1–15.3.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If the original estimate/interval and calculation definition become available, separately compare arm-specific denominators/dispersion and clinical criteria." }, { "item_id": "N17", "question_type": "Clinical importance", "question": "Is there a verified Hb MCID/important difference?", "needed": "A justified important between-group difference for the selected B12-deficiency anemia, day-90 Hb and active comparator", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting effect magnitude under statistical conventions into importance to patients or failure to meet an MCID.", "application_exception": "Do not arbitrarily adopt a common minimum number of participants, duration or trial count as a sufficiency criterion.", "criterion": "Distinguish the empty verified_between_group_MCID value from the existing statistical magnitude code.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M15 §15.3.1–15.3.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Obtain evidence of importance for this population/scale/time point and compare it separately with the relevant effect/CI." }, { "item_id": "N18", "question_type": "Superiority, equivalence and NI", "question": "Was the authors' interpretation of similarity converted into verified equivalence?", "needed": "Original authors' interpretation, superiority/equivalence/NI design and prespecified margins/analysis requirements", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid establishing equivalence, NI or an effect of 0 from nonsignificance or similar numerical values.", "application_exception": "The selected question concerns superiority; do not invent an NI margin or perform a new NI reassessment.", "criterion": "Preserve the authors' interpretation together with the empty formal_Hb_NI_margin and the several establishment flags set to false.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M15 §15.3.1–15.3.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If an NI/equivalence question is separately assigned, review its prespecified margin, analysis and precision against the relevant requirements." }, { "item_id": "N19", "question_type": "Allocation and completer denominators", "question": "Which denominators do 70/10/26/34 each represent?", "needed": "70 enrolled, 10 lost to follow-up after day10, oral 26/IM34 analyzed, original allocation by arm and numbers measured at each time point", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid using completer counts as original allocation counts or counts for all time points/safety analyses.", "application_exception": "Preserve the historical denominators; do not calculate and fill in dropout rates, participant totals or original denominators by arm in this review.", "criterion": "Distinguish enrollment, attrition and completer analysis from unverified original allocation by arm.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Link the original flow diagram, arm-specific visit/analysis denominators and handling of missing data to the outcome of interest." }, { "item_id": "N20", "question_type": "Missing data and analysis population", "question": "Can the effect of assignment/ITT be verified from completer results?", "needed": "Reasons for losses/distribution by arm, relationship to outcomes, ITT/imputation, sensitivity/PP definitions and estimand", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid calling completer analysis ITT or an effect of full adherence.", "application_exception": "Do not conclude that a small sample/missing data invalidate the results or imply a specific direction of bias.", "criterion": "Show the limitations on interpreting results arising from the exclusion of 10 participants and unverified ITT/imputation.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Obtain arm-specific losses/original outcomes, the planned analysis and sensitivity analyses for missing data." }, { "item_id": "N21", "question_type": "Design and allocation", "question": "Have both block randomization and implementation of concealment been verified?", "needed": "Single-center parallel active-control design, block allocation/concealment implementation, baseline balance and original Methods", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid claiming that allocation/confounding issues are resolved by the randomized label alone.", "application_exception": "Do not convert unreported concealment into confirmed absence of concealment or an official RoB result.", "criterion": "Distinguish the reported randomized open-label design from unverified actual concealment.", "basis": "M08 §8.1–8.2.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Compare original allocation implementation and baseline balance with the Hb outcome of interest." }, { "item_id": "N22", "question_type": "Open-label regimens and measurement", "question": "Were the limitations of open-label routes and the objectivity of Hb reviewed separately?", "needed": "Patient/clinician/assessor blinding, administration differences, Hb measurement and changes in concomitant treatment", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid dismissing the open-label design because Hb is objective, or automatically judging the entire trial a failure.", "application_exception": "Endoscopy blinding does not demonstrate assessor blinding for the Hb outcome.", "criterion": "Link the actual oral fruit juice and nurse-administered IM to objective Hb and unverified assessors.", "basis": "M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 Table 8.2.a, M03 §3.2.4; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Compare route-specific care, changes in concomitant treatment and implementation of Hb assessment against the original records." }, { "item_id": "N23", "question_type": "Registration, protocol and SAP", "question": "Were S01's prespecified plan and actual results compared?", "needed": "S01 registration, protocol, SAP, primary time point/analysis, multiplicity and amendment history", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting an unavailable plan into nonregistration or absence/confirmation of selective reporting.", "application_exception": "Do not link other NCT/OB12 plans as S01 registration.", "criterion": "Distinguish unverified prespecified plans from actual article reporting and differences in the lists.", "basis": "M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; M08 Table 8.2.a, M04 §4.6.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "After verifying identity, compare S01's actual registration/plan/history with its Hb reporting." }, { "item_id": "N24", "question_type": "Reports and trial families", "question": "Are 28 original articles, index records and reviews being counted as 28 replications?", "needed": "The same DOI/PMID for S01/S02, OB12 original article/protocol/supplementary leads, report types and family links", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid double-counting bibliographic records, indexes, reviews and registry access attempts as independent trials.", "application_exception": "Do not calculate new unique trial/participant totals; leave unconfirmed family identities unconfirmed.", "criterion": "Explain the same S01 family and different report roles using the exact retained bibliographic records.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Verify each report's family identity by comparing original registration, institutions/recruitment periods and participant overlap." }, { "item_id": "N25", "question_type": "Replication of the same question", "question": "Are other B12 studies being called replications of the same day-90 Hb result?", "needed": "Unique direct comparisons matching the population, product, route, active comparator and day-90 Hb/denominators", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid creating independent replication from similar results involving other forms, populations or endpoints.", "application_exception": "Preserve the historical R1 code, but do not use it as certification of strong confirmatory evidence or as a new independent trial count.", "criterion": "Separate the single direct family within the current narrow boundary from eligibility limitations of other studies.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If a new directly eligible comparison is authorized/obtained, compare family-specific criteria and opposing results together." }, { "item_id": "N26", "question_type": "Favorable opposing evidence", "question": "Are Gupta2025's favorable Hb results and the reason for exclusion both present?", "needed": "S06 Hb results in anemic women, confirmed B12-deficiency anemia stratum/background IFA, product/denominators/duration", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid transferring only favorable results to the target population or erasing results by retaining only the fact of exclusion.", "application_exception": "Do not newly read the S06 PDF or invent a confirmed stratum/quantitative results to fill gaps in this review.", "criterion": "Preserve the lead to favorable Hb results together with exclusion because a confirmed B12-deficiency anemia stratum is unverified.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Compare original S06 eligibility, strata/product/background treatment and exact Hb results as a separate eligibility question." }, { "item_id": "N27", "question_type": "Unfavorable opposing evidence", "question": "Are Tandon2022's results unfavorable to oral treatment and the reason for pediatric exclusion present?", "needed": "S13 pediatric nutritional megaloblastic anemia, direction of Hb findings in the original abstract and difference from the adult boundary", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid erasing unfavorable results or combining them with effects in adults.", "application_exception": "Pediatric exclusion is not deletion/invalidation of unfavorable results or a judgment of harm in adults.", "criterion": "Retain both the unfavorable direction of Hb findings in the pediatric trial and its exclusion from application.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Obtain the population/regimen/time points, denominators and results within their original scope, and link them to a separate pediatric question." }, { "item_id": "N28", "question_type": "Adjacent endpoints and routes", "question": "Are serum B12, Hct and other routes substituting for the selected Hb outcome?", "needed": "Roles of reports on Kuzminski Hct, OB12 serum normalization, metabolism/preferences/RYGB and other forms/intranasal/IV administration", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid satisfying endpoint and product/route eligibility merely through similarity of blood-measure or molecular names.", "application_exception": "Retain the original bibliography/access record, but do not use it as a basis for creating unreported Hb values.", "criterion": "Link endpoint/population/route limitations of each adjacent study to the original locations.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M03 §3.2.4; internally defined boundaries for extending the claim", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "After actually obtaining each original Methods/table and population-specific Hb results, separately review whether it addresses the same question." }, { "item_id": "N29", "question_type": "Reviews and unaccessed leads", "question": "Were review summaries/registry shells used as original trial results?", "needed": "Material types and reading scope for unaccessed S09–S11, reviews/evidence tables S15–S19 and registry/supplementary leads S23–S28", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid calling review bibliographies and shells/pointers actual plans, full texts or independent replications.", "application_exception": "Do not convert unverified information into nonregistration, absence of studies or absence of corrections.", "criterion": "Distinguish each material's historical access, nonreading, unverified results and direct/indirect role.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; M08 Table 8.2.a, M04 §4.6.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "In an authorized update, compare identities, content and families of original reports, official registry records and supplements." }, { "item_id": "N30", "question_type": "Funding and product supply", "question": "Does I1 verify actual mixed funding or independence?", "needed": "S01 research funding, product supply, author disclosures/institutions and original Funding/COI", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting a rule-based value for unverified funding into actual mixed funding, independence or absence of COI.", "application_exception": "Do not transfer funding or product-supply information from other OB12/review materials to S01, or exclude automatically on the basis of COI.", "criterion": "Separate unverified funding/product supply from the meaning of the historical I1 fallback.", "basis": "Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not guarantee every detail of this item", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Check original S01 funding/supply, author disclosures, relevant institutions and family information." }, { "item_id": "N31", "question_type": "Historical assessment and methods", "question": "Are C, 46, E~ and the empty precision value being read as a new assessment or an MCID?", "needed": "Boundaries of the original grade/score/Caution, axes, document quality A, self-review and method implementation", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting the original score/codes into checklist-based efficacy probabilities, fulfillment rates or official GRADE certification.", "application_exception": "Do not calculate scores, grades, dispersion or new sufficiency numbers, or judge efficacy by the number of criteria.", "criterion": "Distinguish historical C46 and B/S/R1/I1/E~/B2/empty precision from document quality and review scope.", "basis": "M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; M15 §15.3.1–15.3.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If an individual correction is authorized, review it as a separate event preserving the complete original assessment, before/after values and reasons." }, { "item_id": "N32", "question_type": "Current and historical reading", "question": "Is this review's summary reading distinguished from historical full-text transcription access?", "needed": "Exact pointers in the currently stored manuscript, 28 bibliographic records/locations and historical material types/access levels/dates", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid retroactively treating historical reading of transcriptions, PDFs and official documents as actual original-source reading in this review.", "application_exception": "Do not newly label all currently unattempted external materials as inaccessible.", "criterion": "Keep the actual reading of retained summaries in this review and the original historical access on 2026-09-16 as separate materials/links.", "basis": "M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If original-material acquisition/actual reading is authorized, separately record the edition, sections read and file SHA for each material type." }, { "item_id": "N33", "question_type": "Original PDF/transcription comparison", "question": "Has a current visual comparison with the publisher PDF been performed?", "needed": "Original publisher PDF, repository transcription, tables/units/footnotes and a visual-comparison event", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting a repository full-text transcription into direct verification of the publisher PDF.", "application_exception": "The file preserved in this review is a limited stored summary, not the original bytes of the full text.", "criterion": "Retain historical S01 transcription access separately from the unverified visual comparison with the publisher PDF.", "basis": "M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "After authorized/lawful acquisition of the original PDF, compare actual tables, footnotes and text against the transcription and record the edition/hash." }, { "item_id": "N34", "question_type": "Search, registration and publication status", "question": "Are gaps in the current retained scope being described as absence of current studies?", "needed": "Evidence cutoff 2026-09-16, original search/access summaries, actual reading in this review and scope regarding unpublished material/corrections/retractions", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid overstating conversion of stored materials as a current exhaustive search on 2026-10-05.", "application_exception": "The existence of an original search-log path does not mean that the log/DB export was read in this review.", "criterion": "Specify the historical actual-search summary, 0 new searches in this review and the unverified scope regarding DBs, registration and corrections.", "basis": "M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; M08 Table 8.2.a, M04 §4.6.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "In a separately authorized update, record actual search expressions, scope, failures and original responses for searches/registration/corrections as a new event." }, { "item_id": "N35", "question_type": "Harm definitions and collection", "question": "Does no reported treatment-related adverse reaction mean total AE0?", "needed": "S01 treatment-related AE definition, collection method, all AEs/SAEs, discontinuations, severity and original denominators", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting the original sentence into complete event accounting or absence of all harms.", "application_exception": "Do not delete efficacy results because harms were not reported or assign a new safety grade.", "criterion": "Display no reported treatment-related events separately from unverified total events, collection and discontinuations.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Check the original Tolerability section, collection/adverse-event tables and discontinuation/loss records." }, { "item_id": "N36", "question_type": "Safety denominators and losses", "question": "Does safety coverage include the 10 participants outside the 26/34 completers?", "needed": "Total exposure/safety denominators, numbers of affected people/events, 90-day/early follow-up and safety of the 10 lost participants", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid using a related-AE narrative limited to completers as an incidence estimate for all enrolled participants.", "application_exception": "Preserve the original denominators; do not calculate incidence, an upper bound for rare harms or AEs among lost participants in this review.", "criterion": "Show the denominators/duration of the completer narrative and the safety gap for those lost to follow-up.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Link arm-specific exposure/safety analysis counts, reasons for losses/events and follow-up duration to the original records." }, { "item_id": "N37", "question_type": "Harms: timing, comparison and alternatives", "question": "Does a no-event narrative verify comparative safety or causal safety of oral treatment?", "needed": "Arm-specific events; timing of exposure, onset, discontinuation and recovery; IM comparator; concomitant treatment; baseline/loss-related alternative explanations", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid promoting reporting/nonreporting after exposure into comparative risk or causal safety.", "application_exception": "Do not infer a risk difference, dechallenge/rechallenge or absence of alternative explanations solely from no related AEs being reported in both arms.", "criterion": "Distinguish the 90-day active-comparator context from unverified event timing, total accounting and alternative explanations.", "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.2 questions about harms by study design; details of temporal relationships are internally designed; M19 §19.2.2–19.2.4, M03 §3.2.3; internal application; M19 §19.2.2–19.2.4 design considerations; detailed confounding records are internally designed; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Check material that permits comparison of original arm-specific events/timing with concomitant treatment, baseline risks and missing data." }, { "item_id": "N38", "question_type": "Official safety materials and independent events", "question": "Are official notices/labels being counted as independent clinical replications of harms?", "needed": "Material types/molecules, underlying events, denominators and families for S20 ODS, S21 cobalt notice and S22 injection label", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting the authority of official documents or repeated citations into new independent events/incidence.", "application_exception": "Distinguish the chemical forms/routes in each notice; do not label this review as a new check of current full texts or underlying event data.", "criterion": "Keep historical bibliographies/boundaries of safety documents separate from clinical-trial denominators/events.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.6.1–4.6.2; adaptations for harm materials are internally designed; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "In an authorized update, compare notice versions, original events/denominators and relationships among repeated citations." }, { "item_id": "N39", "question_type": "UL and safety interpretation", "question": "Does an unset UL guarantee unlimited safety?", "needed": "S20 B12 UL explanation and reasons for no established UL; boundaries of the selected regimen's duration/population and actual events", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid converting the absence of an established upper safety limit into safety at every dose or for every person.", "application_exception": "The study schedule/Caution is not an instruction for personal dosing, injections, transfusions or medication changes.", "criterion": "Specify the distinction between no established UL and established safety, and the historical Caution.", "basis": "M19 §19.1.2–19.2.4; internal application; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If asking about safety by dose, duration or vulnerable population, review the relevant direct evidence under separate criteria." }, { "item_id": "N40", "question_type": "Cobalt and injection warnings", "question": "Were the label's chemical form/route transferred into oral-treatment incidence?", "needed": "S21 scope of cobalt sensitivity for cyano/hydroxo; S22 injection context for Leber/early hypokalemia", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid transferring a specific injection warning into observed incidence for all oral treatments/chemical forms.", "application_exception": "The existence of a warning and actual S01 events, causality and incidence are different information.", "criterion": "Link original warnings for each chemical form/route and special circumstance to their own scope.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.2.2–19.2.4 design considerations; detailed confounding records are internally designed; M19 §19.1.2–19.2.4; internal application; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "Check original label/notice editions and underlying events separately from direct oral-treatment/special-population evidence." }, { "item_id": "N41", "question_type": "Long-term harms and vulnerable populations", "question": "Do short-term adult data answer questions about rare harms or long-term/special-population safety?", "needed": "Long-term/rare events, exposure/baseline risk in hepatic or renal disease, pregnancy/lactation and children, denominators and suitable designs", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid extending a population limited to 90 days into safety for all special populations/durations.", "application_exception": "Preserve the selected efficacy evidence; do not require every rare-harm study as a fulfillment condition for that Hb result.", "criterion": "Show the original 90-day/nonpregnant, nonlactating adult scope and unverified safety beyond it.", "basis": "M19 §19.1.2–19.2.4; internal application", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If a safety extension is requested, separately review observational/comparative data appropriate to the population, duration and events." }, { "item_id": "N42", "question_type": "Direct dose optimization", "question": "Must a same-schedule comparison also answer the optimal-dose question?", "needed": "If an optimal-dose question is added: direct dose/active-amount comparisons, actual exposure and Hb/harm estimates", "role": "Extension boundary; required for an optimal-dose claim", "role_reason": "Needed to avoid extending a comparison of two regimens with the same nominal schedule into dose response or optimal dosing.", "application_exception": "Do not require trials of multiple doses for the narrow 90-day route/regimen comparison.", "criterion": "Explain that the selected question is not an optimal-dose comparison, with the original dose and boundaries.", "basis": "M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If optimization is separately requested, design direct dose contrasts and harm assessment in the same population/product." }, { "item_id": "N43", "question_type": "Long-term maintenance and effects of discontinuation", "question": "Were lifelong maintenance/discontinuation effects mixed into the 90-day question?", "needed": "If a long-term maintenance/discontinuation question is added: actual follow-up, post-discontinuation Hb and exposure/denominators", "role": "Extension boundary; required for maintenance/discontinuation claims", "role_reason": "Needed to avoid converting a lifelong monthly plan into lifelong effects or maintenance after discontinuation.", "application_exception": "Do not require lifelong follow-up for the selected 90-day comparison.", "criterion": "Separate the selected 90-day question from questions about long-term effects or effects of discontinuation.", "basis": "M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If a long-term extension is requested, obtain actual exposure/follow-up and arm-specific outcomes, rather than plans." }, { "item_id": "N44", "question_type": "Extension to clinical events", "question": "Is Hb an effect on fatigue, transfusion, death or daily functioning?", "needed": "If an event/quality-of-life claim is added: the relevant direct endpoint, time point/denominators and importance", "role": "Extension boundary; required for event/quality-of-life claims", "role_reason": "Needed to avoid converting a laboratory surrogate into an effect on clinical events or patient functioning.", "application_exception": "Do not require an event trial for a question about the Hb value itself.", "criterion": "Explain the boundary between laboratory Hb S and separate event/function endpoints.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M03 §3.2.4; internally defined boundaries for extending the claim", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If extension to events is requested, separately obtain between-group data on the direct endpoint of interest." }, { "item_id": "N45", "question_type": "Extension to other products and routes", "question": "Are effects of tablets or other chemical forms/routes being compulsorily combined?", "needed": "If a separate product/route claim is added: direct Hb comparison for that product, population and regimen", "role": "Extension boundary; required for claims about other products/routes", "role_reason": "Needed to avoid extending the actual ampule+fruit juice comparison to all B12 products/routes.", "application_exception": "Do not require trials of other products for the selected regimen or erase gaps in original product details with NA.", "criterion": "Show the boundary between actual Dodex and extension to methyl/hydroxo/adeno, tablets/sublingual/intranasal/IV administration.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed; M03 §3.2.4; internally defined boundaries for extending the claim", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If a separate regimen question is authorized, first fix the direct Hb criteria for each identity/route." }, { "item_id": "N46", "question_type": "ID and publication metadata", "question": "Are original ID/code and deployment expressions being read as the publication status of this review?", "needed": "KO needs_id_assignment, null semantic, original automatic codes/assigned, server_deployed/not-deployed expressions and original URLs/dates", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid hiding differences in original expressions or using historical deployment flags to say that this sheet has been publicly published.", "application_exception": "Do not silently correct original values or arbitrarily establish authority precedence between general metadata and a specific semantic field.", "criterion": "Preserve differing original identity/deployment expressions and separate them from this local unpublished work.", "basis": "M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If an identity/deployment correction is separately authorized, record the complete original, authority/decision and before/after values as an event." }, { "item_id": "N47", "question_type": "Updates and traceability", "question": "Are there update rules that preserve original text, criteria and opposing values?", "needed": "Original revision triggers, cutoff/actual review dates, prior freezing of criteria, exact values/pointers/SHA and before/after events/versions", "role": "Required (selected day-90 Hb comparison)", "role_reason": "Needed to avoid silently overwriting historical values, unfavorable results or criteria versions with new material/corrections.", "application_exception": "New research, calculations, reassessments and automatic deployment are not inherited by the current conversion task.", "criterion": "Link each row's material, locations read, necessary criteria and reasons for updates with preservation of the complete original.", "basis": "M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design", "condition_origin": "Development criteria designed with knowledge of the current 3113 retained materials after actually reading them individually. Not blinding, clinical preregistration or independent clinical certification", "proposed_research": "If authorized original PDFs, plans, direct trials, funding information or corrections arrive, review them while preserving a separate event, criteria version and before/after values." } ] }