{
  "schema_version": "chamgap-public-criteria-1.0",
  "title": "Oral saffron stigma extract × Cognition in mild-to-moderate Alzheimer's disease",
  "language": "en",
  "translation_date": "2026-10-28",
  "criteria_version": "1.1",
  "criteria_date": "2026-10-05",
  "condition_origin": "Chamgap's own application conditions",
  "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 conditions and reasons for changes; distinguish intervention variants.",
      "review_level": "Retained method-application records were reused. External originals were not reread and method content was not reassessed."
    },
    {
      "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": "Link studies and reports separately; do not omit studies solely because results are unreported.",
      "review_level": "Retained method-application records were reused. External originals were not reread and method content was not reassessed."
    },
    {
      "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": "Fix the result and effect of interest when examining randomization, deviations, missingness, measurement and selective reporting.",
      "review_level": "Retained method-application records were reused. External originals were not reread and method content was not reassessed."
    },
    {
      "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": "Retained method-application records were reused. External originals were not reread and method content was not reassessed."
    },
    {
      "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": "Harm questions may require different designs, populations and follow-up from efficacy questions. Case reports do not establish incidence.",
      "review_level": "Retained method-application records were reused. External originals were not reread and method content was not reassessed."
    }
  ],
  "status_dictionary": {
    "Partly verified": "Some retained information and the remaining required material are displayed together.",
    "Unverified": "The specified condition cannot be established within the retained scope; this means neither an effect of 0, 0 studies worldwide nor established safety.",
    "Review incomplete": "Original-material comparison/search was not performed within the authorized scope.",
    "Not reported": "A scope-limited status meaning that an item is not reported in the specific material/section actually read.",
    "Inaccessible": "Used only for material actually accessed unsuccessfully. Not assigned to clinical material in this work.",
    "Insufficient evidence matching the conditions": "Used only after reviewing relevant research within a defined scope and finding insufficient evidence to answer the condition. Not applied universally here.",
    "Not applicable": "Separate events, optimal dose and long-term extensions are not additional mandatory conditions for the selected 16-week cognitive comparison.",
    "Conflicting data": "Used when material addressing the same question, time and analysis is difficult to reconcile. Different numbers in reviews alone do not qualify.",
    "Met": "The stated retained content, boundary and attribution are verified; this is not clinical confirmation, external full-text reading or revalidation of the original verdict."
  },
  "requirements": [
    {
      "item_id": "N01",
      "question_type": "Evidence condition",
      "question": "Which saffron, Alzheimer's disease and cognition comparison is being checked?",
      "needed": "Specific extract, population, 16-week ADAS-cog, placebo and original claim boundary.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid merging all related saffron effects into a single status.",
      "application_exception": "Active-drug comparisons and add-on trials are not replications of the same placebo question.",
      "criterion": "Link the specific stigma extract's 16-week ADAS-cog versus placebo question to the retained original.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare candidate material with the exact ingredient, population, comparator, scale and time."
    },
    {
      "item_id": "N02",
      "question_type": "Evidence condition",
      "question": "Do the core trial population and medication restrictions match the original question?",
      "needed": "Diagnosis, age, MMSE, inclusion/exclusion and antidementia-medication restrictions.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid applying the findings to all patients with dementia in routine care.",
      "application_exception": "Do not extend to MCI, dementia prevention or all patients receiving concomitant drugs.",
      "criterion": "Distinguish the core population, selection and medication restrictions from unverified representativeness.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Link selection criteria, baseline tables and medication restrictions to the actual results."
    },
    {
      "item_id": "N03",
      "question_type": "Evidence condition",
      "question": "How far are S1's plant part, extraction specifications, detailed batch, content and manufacturing quality verified?",
      "needed": "Stigma, extraction solvent, capsule, standardization and the actual trial product.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid transferring results to tea, foods or isolated constituents.",
      "application_exception": "Other extracts, crocin/safranal alone and combination products are separate.",
      "criterion": "Link the reported stigma, 80% ethanolic dried extract, capsule and standardization specifications, separately assessing original verification of detailed batch, content and manufacturing quality.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare product specifications and batch information with the applicability of the trial results."
    },
    {
      "item_id": "N04",
      "question_type": "Evidence condition",
      "question": "Were the core trial route and dose linked?",
      "needed": "Oral capsule, amount per 1 administration, frequency, total amount and actual exposure records.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid turning trial specifications into personal dosing instructions.",
      "application_exception": "Nominal dose does not establish quantitative adherence.",
      "criterion": "Distinguish the reported oral 15 mg, 2 times daily, from unverified actual exposure.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare administration specifications, adherence and discontinuation records by group."
    },
    {
      "item_id": "N05",
      "question_type": "Evidence condition",
      "question": "Do administration duration and the selected result time match?",
      "needed": "16-week administration, ADAS-cog assessment time and post-discontinuation material.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid merging results at different durations as the same effect.",
      "application_exception": "S2's 22 weeks and S3's 12 weeks do not replace the core 16-week result.",
      "criterion": "Link core 16-week administration to the ADAS-cog result.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Separate assessment schedules, end-of-treatment and post-discontinuation follow-up."
    },
    {
      "item_id": "N06",
      "question_type": "Evidence condition",
      "question": "Were the core placebo and antidementia-medication restrictions distinguished?",
      "needed": "Comparator product, antidementia-medication restrictions, rescue treatment and changes by group.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid attributing differences in concurrent treatment to saffron.",
      "application_exception": "Appearance matching does not guarantee taste/smell matching or agreement in all concomitant treatments.",
      "criterion": "Link the actual placebo and medication restrictions to unverified concomitant-treatment deviations.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Verify comparator specifications, treatment changes and their handling in the analysis of the effect of interest."
    },
    {
      "item_id": "N07",
      "question_type": "Evidence condition",
      "question": "Is the donepezil active comparison being turned into placebo-relative efficacy or equivalence?",
      "needed": "S2's actual comparator, duration, endpoints, design and equivalence plan.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to distinguish no significant difference from equivalence.",
      "application_exception": "Retain active-comparator material as a different comparison.",
      "criterion": "S2 is a 22-week donepezil active comparison and does not certify noninferiority or placebo-relative efficacy.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Review the active comparison's advance noninferiority criteria, models and intervals as a separate question."
    },
    {
      "item_id": "N08",
      "question_type": "Evidence condition",
      "question": "Were S3's nonsignificant MMSE result and different concomitant-treatment conditions both retained?",
      "needed": "Donepezil co-treatment, 12-week MMSE, denominators, result and role.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid retaining only favorable direct results.",
      "application_exception": "Do not turn nonsignificance into an effect of 0 or inflammatory markers into cognitive effects.",
      "criterion": "Explain the differences between S3 and S1 in co-treatment, scale and time.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "First compare whether results address the same question, then acquire separate estimates and intervals."
    },
    {
      "item_id": "N09",
      "question_type": "Evidence condition",
      "question": "Were the ADAS-cog definition, direction and version verified?",
      "needed": "16-week change, improvement with lower scores, exact version, translation and assessment procedures.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to distinguish the cognitive endpoint itself from other scales and events.",
      "application_exception": "Do not reclassify it as a biological surrogate merely because it is a test.",
      "criterion": "Distinguish the direction of the cognitive endpoint from the verified scope of measurement details.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Link scale version, language, assessor training and schedule to the result table."
    },
    {
      "item_id": "N10",
      "question_type": "Evidence condition",
      "question": "Were the core change values, SD and direction preserved?",
      "needed": "Group-specific 16-week ADAS-cog mean changes, SD and original location.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to distinguish final values, within-group change and between-group effects.",
      "application_exception": "Do not convert mean differences into individual probabilities of improvement.",
      "criterion": "Attribute the retained changes −3.69±1.69 versus +4.08±1.34 and SD to the relevant comparison.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Verify original tables, denominators, definitions and rounding before reviewing numerical attribution."
    },
    {
      "item_id": "N11",
      "question_type": "Evidence condition",
      "question": "How far are the reported change-score, repeated-measures and final-value tests and the authors' explanation/correction of the final-value inconsistency verified?",
      "needed": "Analysis, time, P, t/df and correction records for each test.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to distinguish different tests from actual internal reporting inconsistencies.",
      "application_exception": "Do not call every difference in P a conflict before checking whether it concerns the same question.",
      "criterion": "Link change-score P<.0001, repeated-measures P=.04 and the historical final-value inconsistency to their respective tests; separately assess original author explanations or corrections.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Acquire test-specific original tables, models and correction material, comparing each test's meaning."
    },
    {
      "item_id": "N12",
      "question_type": "Evidence condition",
      "question": "How far are endpoint-specific execution, denominators and sensitivity verified for 23/23 allocation and paper-defined ITT/LOCF?",
      "needed": "Randomized, completed and analyzed n, ITT definition, LOCF and effect of interest.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid automatically substituting randomized counts for analysis denominators.",
      "application_exception": "Do not expand the paper's analysis label into certification of modern complete ITT.",
      "criterion": "Preserve recorded 23/23 allocation, paper-defined ITT/LOCF and analysis df44, assessing endpoint-specific analysis sets, execution, sensitivity and current original-data comparison.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare participant flow, actual endpoint-specific analysis sets and missing-data models."
    },
    {
      "item_id": "N13",
      "question_type": "Evidence condition",
      "question": "How far are group-specific dropout/completion records, other missing-data reasons, death handling and sensitivity verified?",
      "needed": "Group-specific dropout, reasons, death and distinction between completion and analysis.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid turning subtraction into an author-observed completion table.",
      "application_exception": "Do not calculate new dropout rates or completion counts.",
      "criterion": "Retain recorded 1/23 versus 3/23 dropouts and the historical subtraction behind 22/20 completers, assessing other missing-data reasons, death handling and sensitivity analyses.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Link group-specific flowcharts, missing-data reasons and death handling to results."
    },
    {
      "item_id": "N14",
      "question_type": "Evidence condition",
      "question": "Were the validity of LOCF missing-data assumptions and sensitivity to other handling verified?",
      "needed": "Missing-data assumptions, imputation method, reasons by group and sensitivity results.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid claiming no missing-data problem merely because numerical results are complete.",
      "application_exception": "Do not score LOCF use itself as proven null efficacy or a specified bias magnitude.",
      "criterion": "Retain original LOCF use and missing-data uncertainty, assessing whether reasons by group, assumption validity and sensitivity to alternative handling were verified.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare missing-data and sensitivity analyses appropriate to the effect of interest with randomized results."
    },
    {
      "item_id": "N15",
      "question_type": "Evidence condition",
      "question": "Was the arithmetic −7.77-point difference distinguished from an author-adjusted effect?",
      "needed": "Original means, historical arithmetic, estimand definition and adjusted model.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid turning an existing calculation into a formal between-group effect reported by the authors.",
      "application_exception": "No new effect-size calculation is performed in this work.",
      "criterion": "Identify −7.77 as the historical simple difference between published mean changes.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare original paper estimates, models and intervals with the existing arithmetic."
    },
    {
      "item_id": "N16",
      "question_type": "Evidence condition",
      "question": "How far are assumptions behind the editorial conditional interval and an author-reported 95% CI for the same endpoint verified?",
      "needed": "Interval calculator, assumptions, rounding, denominators, LOCF and the original author interval.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid certifying an original-author interval or clinical precision merely because an interval exists.",
      "application_exception": "Do not rerun t, SE or CI calculations in this work.",
      "criterion": "Preserve the existing independent-group equal-variance t conditional interval's calculator, assumptions, rounding, denominators and LOCF; separately assess original verification of an author-reported 95% CI and its analysis assumptions.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare original author estimates/intervals, assumptions and missing-data sensitivity for the same endpoint."
    },
    {
      "item_id": "N17",
      "question_type": "Evidence condition",
      "question": "Was a clinical-importance threshold for this ADAS-cog difference acquired?",
      "needed": "Validated importance criteria and direct clinical outcomes for the diagnosis, scale and duration.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to distinguish statistical magnitude/significance from clinical importance.",
      "application_exception": "Do not invent MCID, NNT or efficacy percentages or reconfirm EX.",
      "criterion": "Verify applicable importance criteria and their relationship to the result and uncertainty.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Separately review context-appropriate importance evidence and daily-function material."
    },
    {
      "item_id": "N18",
      "question_type": "Evidence condition",
      "question": "Were sequence generation and actual allocation concealment verified?",
      "needed": "Sequence generation, recruitment/allocation responsibilities, concealment and baseline balance.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid treating a randomization label as resolution of all allocation issues.",
      "application_exception": "Do not turn unverified details into evidence of improper allocation.",
      "criterion": "Distinguish recorded computer-generated sequence/codes from unverified execution details.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare recruitment/allocation procedures, registration, baseline tables and results."
    },
    {
      "item_id": "N19",
      "question_type": "Evidence condition",
      "question": "How far are comparator matching, adherence, assessor training and successful blinding verified?",
      "needed": "Appearance, taste/smell, caregiver supervision, assessor training and successful blinding.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to preserve distinct verified scopes for intervention and measurement.",
      "application_exception": "Do not turn a double-blind label into complete verification of actual success.",
      "criterion": "Link recorded appearance matching, supervision and assessment schedules, assessing verification of taste/smell matching, quantitative adherence, assessor training and blinding success.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Acquire product matching, assessment procedures, exposure by group and success checks."
    },
    {
      "item_id": "N20",
      "question_type": "Evidence condition",
      "question": "Were prospective registration/SAP and the selected result compared?",
      "needed": "Time-verified registration, protocol, SAP and scale/time/analysis changes.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid mistaking the page-selected endpoint for a registry primary endpoint.",
      "application_exception": "Unavailable registration is not evidence of nonregistration or manipulated selective reporting.",
      "criterion": "Compare the actual plan with 16-week ADAS-cog analysis and reporting.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Link original registration, timestamps and amendments to the statistical section."
    },
    {
      "item_id": "N21",
      "question_type": "Evidence condition",
      "question": "Were the comparisons in the three reports distinguished from independent replication?",
      "needed": "Report identity, comparator, co-treatment, endpoints, times and family links.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid counting 3 reports as 3 independent replications of the same question.",
      "application_exception": "Do not assume the same participant group solely from shared authors or ingredient.",
      "criterion": "Explain known relationships among S1 placebo, S2 active and S3 add-on comparisons and unverified unique counts.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare report, registry and participant identities to update unique-family links."
    },
    {
      "item_id": "N22",
      "question_type": "Evidence condition",
      "question": "Within which search and review scope is insufficiency described?",
      "needed": "Original review date, search methods, registration/unpublished/correction scope and current input.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid presenting a retained review as a current exhaustive search.",
      "application_exception": "No new search does not mean 0 studies worldwide.",
      "criterion": "Distinguish the original 2026-09-14 review from this retained-material conversion.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Record actual queries, dates and inclusion/exclusion within later authorized scope."
    },
    {
      "item_id": "N23",
      "question_type": "Evidence condition",
      "question": "How far are S1's university/company support, material supply, cash shares, employee authorship, patents and separate COI verified?",
      "needed": "University/company support, material, cash shares, employee authorship, patents and COI.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid automatic exclusion or certification of independence based on funding alone.",
      "application_exception": "Funding institutions and independence of trial replication are separate.",
      "criterion": "Link stated joint support and company material supply, assessing reporting and original verification of cash shares, employee authorship, patents and separate COI.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare grant, material-supply, author, patent and COI documents within the same report."
    },
    {
      "item_id": "N24",
      "question_type": "Evidence condition",
      "question": "How far are funding, product support, employee authorship, patents and COI verified in S2's own documents?",
      "needed": "S2-specific funding, products, employment, patents and COI.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid transferring funding information to another comparison with the same authors.",
      "application_exception": "Do not copy S1's university/company support as verified S2 information.",
      "criterion": "Without inheriting S1 information, assess the existence and actual verification of funding, product, employment, patent and COI material in S2's own documents.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Individually compare S2 funding, material supply, author declarations and trial identity."
    },
    {
      "item_id": "N25",
      "question_type": "Evidence condition",
      "question": "How far were S3's support/COI declaration and separate product-supply, employee-authorship and patent verification completed?",
      "needed": "Grant 62590, author COI declaration, product supply, employee authorship and patents.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to distinguish author declarations from complete independence verification.",
      "application_exception": "A no-COI declaration does not establish absence of bias.",
      "criterion": "Link recorded grant 62590 and the authors' no-COI declaration, assessing whether separate product-supply, employee-authorship and patent verification material was confirmed.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Link support, product, author and patent material by report."
    },
    {
      "item_id": "N26",
      "question_type": "Evidence condition",
      "question": "How far are S1's reported adverse-event/death counts and event definitions, collection completeness and severity verified?",
      "needed": "Event definitions, people denominators by group, duration, severity and collection.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid turning small-trial records into a statement that no serious events occurred.",
      "application_exception": "Do not calculate new rates, risk ratios or NNT.",
      "criterion": "Retain hypomania 2/23 versus 0/23, dry mouth 3/23 versus 1/23 and 1 placebo-group death, separately assessing verification of definitions, people denominators, duration, severity and collection completeness.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Link original safety tables, denominators, collection procedures and discontinuation reasons."
    },
    {
      "item_id": "N27",
      "question_type": "Evidence condition",
      "question": "Were harm collection and onset/recovery/discontinuation times acquired?",
      "needed": "Collection system, event dates, severity, discontinuation, recovery and omissions.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid certifying complete collection or causality from event counts alone.",
      "application_exception": "Do not infer unverified times, recovery or re-exposure.",
      "criterion": "Link actual event collection and timing/discontinuation details to original material.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare the safety section, event-specific timelines and all dropout reasons."
    },
    {
      "item_id": "N28",
      "question_type": "Evidence condition",
      "question": "Was direct harm material for concomitant drugs, co-exposures and special populations verified?",
      "needed": "Direct harm material for concomitant drugs, co-exposures, pregnancy/lactation and liver/kidney disease.",
      "role": "Supplementary; required for the relevant safety extension",
      "role_reason": "Needed to avoid extending short-term records in a narrow population to all safety questions.",
      "application_exception": "Do not infer absence of events with other drugs or populations.",
      "criterion": "Preserve recorded trial medication restrictions while assessing verification and applicability of direct harm material for concomitant drugs, co-exposures, pregnancy/lactation and major liver/kidney disease.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Separately review population, exposure and follow-up appropriate to the required harm question."
    },
    {
      "item_id": "N29",
      "question_type": "Evidence condition",
      "question": "Was direct exposure, event, denominator and follow-up material to assess long-term/rare harm beyond 16 weeks verified?",
      "needed": "Long-term exposure, rare events, denominators, follow-up and appropriate collection design.",
      "role": "Supplementary; required for the relevant long-term harm question",
      "role_reason": "Needed to avoid excluding rare/long-term risks from small short-term results.",
      "application_exception": "Do not impose all long-term harm studies as additional mandatory conditions for the original narrow efficacy question.",
      "criterion": "Do not extend short-term records to exclusion of long-term/rare risks; assess verification of long-term exposure, rare events, denominators, follow-up and suitable collection material.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "When long-term/rare harm questions are needed, review appropriate follow-up, registry and collection designs."
    },
    {
      "item_id": "N30",
      "question_type": "Evidence condition",
      "question": "Are cognitive scores being extended to prevention, slowing progression or medication replacement?",
      "needed": "Boundary between ADAS-cog and prevention, daily function, caregiving, progression or prescription-drug replacement.",
      "role": "Supplementary; required for clinical-event/replacement extensions",
      "role_reason": "Needed to distinguish the selected cognitive-function endpoint from separate clinical questions.",
      "application_exception": "Do not reclassify the cognitive score itself as a surrogate.",
      "criterion": "Separate the current 16-week score question from other extensions.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "For extensions, separately review the relevant events, daily function, progression and replacement comparisons."
    },
    {
      "item_id": "N31",
      "question_type": "Evidence condition",
      "question": "Were optimal dose and persistence after discontinuation verified?",
      "needed": "Direct dose comparisons, post-discontinuation follow-up, prespecified subgroups and separate estimates.",
      "role": "Supplementary; required for dose/persistence extensions",
      "role_reason": "Needed to avoid turning a single trial dose into an optimal dose or persistent effect.",
      "application_exception": "Do not automatically require every extension for the current 16-week comparison.",
      "criterion": "Distinguish nominal 30 mg/day, 16-week results from optimal-dose and persistence questions.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "For extensions, separately review direct dose comparisons, discontinuation and long-term follow-up."
    },
    {
      "item_id": "N32",
      "question_type": "Evidence condition",
      "question": "Were the original C46, P correction and EX review status retained?",
      "needed": "Original grade, score, current/previous axes, corrections and unresolved notices.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid automatically inheriting original values as efficacy judgments for the new table.",
      "application_exception": "Do not turn the S→P correction into revalidation of other axes or the final grade.",
      "criterion": "Preserve original C46, P, EX/CX, grade-revalidation false and pending method review from the retained original.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "For a later verdict request, preserve previous values, evidence and change reasons as a separate event."
    },
    {
      "item_id": "N33",
      "question_type": "Evidence condition",
      "question": "Were historical access descriptions distinguished from actual reading in this work?",
      "needed": "Bibliographic flags, original locations, original review date, current acquisition/reading and file SHA.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid turning provision of original links into current full-text reading.",
      "application_exception": "Do not infer absent access-level, source-location or individual access-date fields from narrative descriptions.",
      "criterion": "Separately display actual retained-summary reading, historical descriptions and unread external material.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "When original material is later acquired, record type, date, location, bytes and actual reading."
    },
    {
      "item_id": "N34",
      "question_type": "Evidence condition",
      "question": "Are material acquisition and condition/verdict revisions distinguished as events?",
      "needed": "Preservation records for full texts, registration, corrections, numbers, condition versions and previous values.",
      "role": "Required (selected 16-week ADAS-cog comparison)",
      "role_reason": "Needed to avoid automatic condition/verdict changes when new material is acquired.",
      "application_exception": "Do not delete originals, unfavorable results or unverified information.",
      "criterion": "Distinguish current retained scope from material and linked items needed for later updates.",
      "basis": "Existing method principles distinguish population, formulation, dose, duration, comparator, cognition measurement, denominators, missingness, between-group analysis, intervals, plans, report relationships, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "Conditions for the specific saffron stigma extract, Alzheimer’s disease, 16-week ADAS-cog and placebo comparison were developed with knowledge of retained content and frozen before application. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Record new material identity, reading and locations, review affected rows and freeze condition revisions before application."
    }
  ]
}