{
  "schema_version": "chamgap-public-criteria-1.0",
  "title": "Nicotinic acid (prescription NIASPAN extended-release tablets) × Mean LDL-C percentage change in primary hypercholesterolaemia",
  "criteria_version": "1.0",
  "criteria_date": "2026-10-05",
  "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 methodological-application records were reused. External originals were not reread and methodological 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": "Distinguish and link studies and reports; do not omit studies solely because outcomes are unreported.",
      "review_level": "Retained methodological-application records were reused. External originals were not reread and methodological 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 outcome and effect of interest, then review randomization, deviations, missing data, measurement and selective reporting.",
      "review_level": "Retained methodological-application records were reused. External originals were not reread and methodological 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 effects, intervals, importance and applicability. Sample size alone does not determine precision.",
      "review_level": "Retained methodological-application records were reused. External originals were not reread and methodological 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 designs, populations and follow-up different from efficacy questions. Case reports do not establish incidence.",
      "review_level": "Retained methodological-application records were reused. External originals were not reread and methodological content was not reassessed."
    }
  ],
  "status_dictionary": {
    "Met": "Identity, attribution and scope for this condition are verified in retained material, separately from clinical sufficiency/certification.",
    "Partly verified": "Some information is verified; actual methods, denominators or procedures remain unresolved.",
    "Unverified": "Required clinical data/values are unverified within this reading scope. This does not mean effect0, harmlessness or unfinished table preparation.",
    "Conflicting data": "Inconsistent reports in original records, distinct from differences in dose/time alone.",
    "Not applicable": "An extension requirement outside the narrow lipid question is inapplicable; not a substitute for unread material.",
    "Not applicable (spaced alias)": "Grey alias for Not applicable.",
    "Unread": "External originals were not directly read in this work, distinct from reading retained summaries.",
    "Review incomplete": "A label for unfinished item-specific table review. This case’s retained-record review is complete, separately from unverified clinical data and unread external originals."
  },
  "condition_origin": "Chamgap’s own application conditions",
  "requirements": [
    {
      "item_id": "N01",
      "question_type": "Separate question",
      "question": "Which NIASPAN LDL-C contrast is retained?",
      "needed": "Exact locations for the assessed claim, claim conditions and editorial scope, and the canonical URL.",
      "role": "Required",
      "role_reason": "Needed to keep this LDL-C marker question separate from the full original multi-lipid assessment.",
      "application_exception": "The subclaim array is empty. Do not automatically generate tables for other doses/endpoints or rewrite 128/2346.",
      "criterion": "Connect the exact assessed claim, formulation, population, diet plus placebo, 2000 mg/day and 16 weeks including titration as one question.",
      "basis": "M03 §3.1, §3.2.1–3.2.4: question-clarification principles; detailed separation rules are locally designed; M03 §3.2.2–3.2.3: reverse labelling and laboratory adaptations are locally designed — case-specific adaptation for the separate question.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "First fix the question and report-eligibility table, then check whether other formulations, TG or clinical-event questions have entered the scope."
    },
    {
      "item_id": "N02",
      "question_type": "Population and selection",
      "question": "Are eligibility criteria and baseline characteristics verified?",
      "needed": "The original article’s inclusion/exclusion criteria, age, baseline table and preceding dietary procedures.",
      "role": "Required",
      "role_reason": "Needed to avoid transferring results in a high-LDL population to all adults, CKD or add-on statin strategies.",
      "application_exception": "Distinguish the planned adult-population question from unverified age/comorbidity details; do not establish a failure of representativeness.",
      "criterion": "Connect primary hypercholesterolaemia with LDL-C >160 mg/dL despite dietary management to actual eligibility and baseline characteristics.",
      "basis": "M03 §3.2.1: detailed population conditions are locally designed; M08 §8.1–8.2.3: local application — case-specific adaptation for population and selection.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Check recruitment criteria and baseline tables against the target and included populations, including selection limitations."
    },
    {
      "item_id": "N03",
      "question_type": "Nutritional status",
      "question": "Does this trial concern correction of B3 deficiency?",
      "needed": "Deficiency-based selection, baseline B3 concentrations and eligibility definitions.",
      "role": "Required (population boundary)",
      "role_reason": "Needed to distinguish nutritional-deficiency treatment from lipid changes at pharmacological doses.",
      "application_exception": "Unreported B3 concentrations do not establish laboratory-confirmed absence of deficiency. Do not require concentration measurement unconditionally for the narrow lipid question.",
      "criterion": "Distinguish a trial not selected for deficiency from the limited scope of unreported B3 concentrations in the abstract/tables.",
      "basis": "M03 §3.2.1: detailed population conditions are locally designed; M03 §3.2.1–3.2.4: dose, duration and effect-modification details are locally designed — case-specific adaptation for nutritional status.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Check whether original recruitment criteria required deficiency; do not pool deficiency-correction evidence as a high-LDL treatment effect."
    },
    {
      "item_id": "N04",
      "question_type": "Ingredient and formulation",
      "question": "What are the selected ingredient, formulation and route?",
      "needed": "Original labelling and product identity for NIASPAN ingredient, ER formulation and oral route.",
      "role": "Required",
      "role_reason": "Needed to avoid assigning the same effects/harms to other molecules or release formulations.",
      "application_exception": "Do not combine general vitamin B3, inositol hexanicotinate, nicotinamide or other formulations as direct evidence.",
      "criterion": "Distinguish oral NIASPAN nicotinic acid extended-release tablets from other B3 forms.",
      "basis": "M03 §3.2.2–3.2.3: reverse labelling and laboratory adaptations are locally designed — case-specific adaptation for ingredient and formulation.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Link product/formulation definitions to result tables and exclude interchange at the same mg dose with immediate-release, sustained-release, no-flush products or nicotinamide."
    },
    {
      "item_id": "N05",
      "question_type": "Dose and actual exposure",
      "question": "Are the target dose, titration and actual administration history verified?",
      "needed": "Arm-specific titration schedules, administration/stopping histories and actual doses.",
      "role": "Required",
      "role_reason": "Needed to avoid treating the target 2000 mg as actual exposure throughout the entire period.",
      "application_exception": "The 1000 mg arm in the same trial is a supporting record; do not create a pooled mean dose.",
      "criterion": "Distinguish the target 2000 mg/day, 4-week titration and actual administration/adherence.",
      "basis": "M03 §3.2.2–3.2.3: reverse labelling and laboratory adaptations are locally designed; M03 §3.2.3, M08 §8.2.2–8.2.3: local application — case-specific adaptation for dose and actual exposure.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Reconstruct exposure during titration and maintenance, then compare actual doses and deviations with intended prescribing."
    },
    {
      "item_id": "N06",
      "question_type": "Comparator strategy",
      "question": "What is the main comparator strategy?",
      "needed": "The common dietary treatment, placebo composition and contemporaneous Table 3 comparison.",
      "role": "Required",
      "role_reason": "The comparison must retain the same time/background to preserve attribution of the LDL-C difference.",
      "application_exception": "Do not substitute AIM-HIGH’s low-dose IR control or statin ± ezetimibe strategy for this placebo.",
      "criterion": "Connect contemporaneous 2000 mg and placebo arms on the same dietary background.",
      "basis": "M03 §3.2.2–3.2.3: reverse labelling and laboratory adaptations are locally designed; M03 §3.2.3, M08 §8.2.2–8.2.3: local application — case-specific adaptation for comparator strategy.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Compare intervention/control strategies and exclude add-on statin TG strategies and other times in the dose-escalation table."
    },
    {
      "item_id": "N07",
      "question_type": "Duration and phase linkage",
      "question": "Is the linkage between abstract and regulatory-table periods/phases verified?",
      "needed": "Original article visit schedules, titration/maintenance phases and an FDA trial-family crosswalk.",
      "role": "Required",
      "role_reason": "Needed to avoid automatically treating different duration labels as errors or replacing them with one value.",
      "application_exception": "The 16-week and 12-week definitions are not automatically conflicting data. Do not establish actual phase correspondence beyond the label.",
      "criterion": "Retain the label’s 16 weeks including 4-week titration and the abstract’s 12-week definition, with limits on exact phase linkage.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3: question-specific outcome adaptations are locally designed; M03 §3.2.1–3.2.4: dose, duration and effect-modification details are locally designed; M04 §4.6.3, M15 §15.3.1–15.3.3: state separation is locally designed — case-specific adaptation for duration and phase linkage.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Compare timelines and visit schedules side by side to verify phase linkage; do not arbitrarily adjust different durations."
    },
    {
      "item_id": "N08",
      "question_type": "Endpoint and unit",
      "question": "What are the selected outcome measure and unit?",
      "needed": "Table 3 mean percentage-change definition, units and baseline reference.",
      "role": "Required",
      "role_reason": "Needed to avoid mixing results measured differently or at other times, even for the same lipid.",
      "application_exception": "Do not replace mean LDL-C change with Table 5 medians/IQR, Table 4 at other times or TG.",
      "criterion": "Connect mean LDL-C percentage change from baseline at 16 weeks with the percentage-point contrast, distinguishing concentration, medians and other lipids.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3: question-specific outcome adaptations are locally designed; M08 Table 8.2.a, M03 §3.2.4: local application — case-specific adaptation for endpoint and unit.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Check table headings, footnotes and measures against original material; record differences between means/medians and concentration/%/percentage points."
    },
    {
      "item_id": "N09",
      "question_type": "Design and allocation",
      "question": "Are the actual design, allocation and concealment implementation verified?",
      "needed": "Original methods for random sequence generation, allocation concealment and the baseline table.",
      "role": "Required",
      "role_reason": "Needed to avoid treating an RCT label alone as resolving allocation and confounding issues.",
      "application_exception": "Do not invent unreported parallel/crossover details or equate unverified allocation concealment with confirmed failure.",
      "criterion": "Show both the abstract’s randomized double-blind fixed-dose placebo-controlled description and unverified allocation implementation.",
      "basis": "M08 §8.1–8.2.3: local application — case-specific adaptation for design and allocation.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Compare sequence generation, enrolment/allocation procedures and concealment implementation with original methods, separating design labels from implementation verification."
    },
    {
      "item_id": "N10",
      "question_type": "Maintenance of blinding",
      "question": "Are maintenance of blinding and arm-specific assessment information verified?",
      "needed": "Participant, staff and assessor blinding procedures and assessments of maintained blinding.",
      "role": "Required",
      "role_reason": "A double-blind label does not replace an actual assessment of maintained blinding.",
      "application_exception": "Warnings about pharmacological-dose flushing alone do not establish unblinding.",
      "criterion": "Distinguish the double-blind description from actual maintenance/assessment procedures.",
      "basis": "M08 §8.1–8.2.3: local application; M08 Table 8.2.a, M03 §3.2.4: local application — case-specific adaptation for maintenance of blinding.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Compare who was blinded, blinding checks and assessor knowledge with original methods, considering limitations for objective lipid outcomes."
    },
    {
      "item_id": "N11",
      "question_type": "Co-treatment and diet",
      "question": "Are individual co-treatment and dietary exposures verified?",
      "needed": "Arm-specific total diet, concomitant drugs/vitamins, rescue treatment and change histories.",
      "role": "Required",
      "role_reason": "A common treatment background does not establish identical individual exposures.",
      "application_exception": "A description that this is not a B-complex intervention does not establish absence of concurrent vitamins in individuals.",
      "criterion": "Distinguish the common dietary background from actual differences in total diet and concurrent vitamins/treatment.",
      "basis": "M03 §3.2.3, M08 §8.2.2–8.2.3: local application; M03 §3.2.2–3.2.3: reverse labelling and laboratory adaptations are locally designed — case-specific adaptation for co-treatment and diet.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Extract co-treatment and dietary records by arm and review their handling in intervention strategies and selected analyses."
    },
    {
      "item_id": "N12",
      "question_type": "Adherence and treatment deviations",
      "question": "Are actual adherence and the analytical handling of treatment deviations verified?",
      "needed": "Arm-specific adherence, stopping/dose changes and handling rules.",
      "role": "Required",
      "role_reason": "Needed to avoid filling missing actual exposure with 100% adherence or a PP analysis.",
      "application_exception": "Unverified adherence details do not establish that the intervention was never administered.",
      "criterion": "Connect prescribed doses to actual adherence, changes, stopping and their handling.",
      "basis": "M03 §3.2.3, M08 §8.2.2–8.2.3: local application; M08 §8.2.2, M15 §15.3.1: local application — case-specific adaptation for adherence and treatment deviations.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Link adherence/stopping tables to actual analysis populations and review differences between assignment-effect and adherence-effect interpretations."
    },
    {
      "item_id": "N13",
      "question_type": "Measurement procedures",
      "question": "Are the LDL-C assay and arm-specific measurement procedures verified?",
      "needed": "Original LDL-C assay, specimen/blood-sampling conditions and visit-specific measurement procedures.",
      "role": "Required",
      "role_reason": "Describing an objective marker does not verify every measurement procedure.",
      "application_exception": "Do not delete observed values because the assay is unverified or assert that laboratory interference actually occurred.",
      "criterion": "Distinguish objective blood-lipid measurement from the actual assay, sampling/visits and measurement limitations.",
      "basis": "M08 Table 8.2.a, M03 §3.2.4: local application; M03 §3.2.4, M15 §15.3.1–15.3.3: question-specific outcome adaptations are locally designed — case-specific adaptation for measurement procedures.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Link the assay and sampling/visit schedules to result tables and review arm-specific differences in methods and timing."
    },
    {
      "item_id": "N14",
      "question_type": "Arm-specific observations",
      "question": "What are the LDL-C values for the two arms at the same time in Table 3?",
      "needed": "FDA Table 3 arm-specific values/footnotes and the article’s 2000 mg LDL result.",
      "role": "Required",
      "role_reason": "Favourable values must also retain their source attribution, without mixing values from other doses.",
      "application_exception": "Do not promote an observed decrease to adequate precision, prevention of clinical events or an individual success probability.",
      "criterion": "Retain mean percentage changes of −14% and −1% with their respective arms, table and time.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3: question-specific outcome adaptations are locally designed; M08 §8.2.2, M15 §15.3.1: local application — case-specific adaptation for arm-specific observations.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Re-extract the agreeing 2000 mg LDL values against the original table/abstract’s arm, endpoint and period definitions."
    },
    {
      "item_id": "N15",
      "question_type": "Historical contrast",
      "question": "What does the retained −13 percentage-point value represent?",
      "needed": "Original difference, unit, method and prohibited-conversion records.",
      "role": "Required",
      "role_reason": "Needed to retain the meaning of existing arithmetic without generating a new effect calculation.",
      "application_exception": "Do not rerun the calculation or reconstruct mg/dL changes without baseline concentrations, ARR, NNT, SMD or CI.",
      "criterion": "Record only the already-retained arithmetic contrast between arm-specific mean percentage changes; do not convert it to an adjusted effect, a new CI or concentration.",
      "basis": "M08 §8.2.2, M15 §15.3.1: local application; M15 §15.3.1–15.3.3: local application; M03 §3.2.4, M15 §15.3.1–15.3.3: question-specific outcome adaptations are locally designed — case-specific adaptation for the historical contrast.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Check the source, common time and direction of the retained arithmetic and whether wording transfers it to an adjusted estimate or clinical risk."
    },
    {
      "item_id": "N16",
      "question_type": "Effect of interest and analysis",
      "question": "Are the analysis population and model for the LDL-C contrast verified?",
      "needed": "Article analysis populations, estimands, models, adjustment and table-specific analysis methods.",
      "role": "Required",
      "role_reason": "Needed to avoid establishing ITT or an adjusted causal difference from an arithmetic contrast alone.",
      "application_exception": "Do not invent ITT/PP or adjusted values or use baseline n as actual analysis n.",
      "criterion": "Link ITT/PP, adjustment and completer/assignment effects to original analyses; do not invent unknown analyses.",
      "basis": "M08 §8.2.2, M15 §15.3.1: local application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4: design-specific adaptations are locally designed — case-specific adaptation for effect of interest and analysis.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Link methods and participants to arm-specific result tables and compare with the effect of interest and missing-data/deviation handling."
    },
    {
      "item_id": "N17",
      "question_type": "Allocation-to-analysis denominators",
      "question": "Are denominators from allocation through analysis verified for each arm?",
      "needed": "Arm-specific recruitment, allocation, completion, analysis and dropout flow, and Table 3 analysis n.",
      "role": "Required",
      "role_reason": "Needed to avoid automatically reusing the total 122 or baseline 41/40 as analysis denominators.",
      "application_exception": "The total 122 includes a 1000 mg arm. The 41/40 values are baseline n, not verified complete analysis n.",
      "criterion": "Distinguish and connect the total 122, key baseline 41/40 and actual analysed/completed/dropout denominators.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4: design-specific adaptations are locally designed; M08 §8.2.2, M15 §15.3.1: local application — case-specific adaptation for allocation-to-analysis denominators.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Reconstruct each arm’s participant flow over time and verify correspondence between total/baseline samples and outcome-specific analysis denominators."
    },
    {
      "item_id": "N18",
      "question_type": "Missing-data handling",
      "question": "Are the reasons for missing data/dropout and their handling verified?",
      "needed": "Arm-specific dropout reasons, missing LDL-C and imputation/sensitivity analyses.",
      "role": "Required",
      "role_reason": "Needed to avoid turning unknown dropout into 0 or an absence of bias.",
      "application_exception": "Do not turn unavailable information into a high dropout rate or a quantified, established bias.",
      "criterion": "Connect missing-data/dropout counts, reasons and handling to the selected analysis.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4: design-specific adaptations are locally designed; M08 §8.2.2, M15 §15.3.1: local application — case-specific adaptation for missing-data handling.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Compare missing-data tables with analysis methods and review whether results under alternative assumptions are available."
    },
    {
      "item_id": "N19",
      "question_type": "Dispersion and CI",
      "question": "Are dispersion and the between-arm CI reported for LDL-C percentage change at the same time?",
      "needed": "Arm-specific percentage-change dispersion, analysis n, between-arm CI and derivation methods.",
      "role": "Required",
      "role_reason": "Needed to avoid reconstructing precision from a significance threshold or an interval for another outcome.",
      "application_exception": "A statement that selected original regulatory tables do not report a value must not be extended to all articles.",
      "criterion": "Verify SD/SE for the relevant percentage changes and the between-arm CI at the same denominator and time.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4: design-specific adaptations are locally designed; M15 §15.3.1–15.3.3: local application — case-specific adaptation for dispersion and CI.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Directly verify dispersion/intervals for the relevant analysis and check for substitution of another table’s IQR or a cardiovascular HR CI."
    },
    {
      "item_id": "N20",
      "question_type": "Testing and significance",
      "question": "Are the exact P value and test definition verified?",
      "needed": "Table 3 testing footnotes, exact P and multiplicity/adjustment methods.",
      "role": "Required",
      "role_reason": "Needed to avoid treating a significance threshold as adequate precision or effect size.",
      "application_exception": "P<0.05 is not an exact P, CI or SD. Do not invent nonsignificant or equivalence results.",
      "criterion": "Distinguish the table threshold P<0.05 from exact P, testing/adjustment and CI.",
      "basis": "M15 §15.3.1–15.3.3: local application; M08 §8.2.2, M15 §15.3.1: local application — case-specific adaptation for testing and significance.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Verify test definitions, analysis populations and comparisons subject to adjustment; do not calculate CI/dispersion from the threshold."
    },
    {
      "item_id": "N21",
      "question_type": "Important difference",
      "question": "Can the between-arm interval be interpreted against a justified important difference?",
      "needed": "The LDL-C contrast CI, evidence for an important difference in this question and interpretation limits.",
      "role": "Required (precision interpretation)",
      "role_reason": "Needed to retain the observed lipid decrease without adding conclusions about sufficient effect or clinical benefit.",
      "application_exception": "Do not create common sample-size, duration or trial-count thresholds or use the original C/46/EX cap as a numerical important-difference criterion.",
      "criterion": "Link the reported CI to evidence for an important difference in this question; do not turn EX(a) into effect0 or failure to reach an MCID.",
      "basis": "M15 §15.3.1–15.3.3: local application; M03 §3.2.4: locally defined extension boundary — case-specific adaptation for important difference.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Review whether a justified important difference and the relevant interval are provided; otherwise, do not judge sufficiency from significance alone."
    },
    {
      "item_id": "N22",
      "question_type": "Plans and registration",
      "question": "Do reported endpoints, times and analyses agree with the original plan?",
      "needed": "Initial registration, protocol, analysis plan and amendment history.",
      "role": "Required",
      "role_reason": "Needed to avoid establishing agreement with a registered 1st (primary) endpoint from the abstract/label alone.",
      "application_exception": "An NCT value of null does not establish nonregistration. An unavailable plan is not definitive evidence of selective reporting.",
      "criterion": "Verify only the portions actually compared between original registration/protocol/analysis plan and reported LDL-C results.",
      "basis": "M08 Table 8.2.a, M04 §4.6.3: local application; M04 §4.5, §4.6.3: current-record conversion limits derive from user scope and local design — case-specific adaptation for plans and registration.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Compare prespecified endpoints, times and analyses in original plans with result tables/articles to review changes and possible selective reporting."
    },
    {
      "item_id": "N23",
      "question_type": "Reports and trial family",
      "question": "At what level are the article and label linked to the same trial family?",
      "needed": "Trial identifiers and population/arm/time crosswalks between the article and FDA trial tables.",
      "role": "Required",
      "role_reason": "Needed to avoid adding the article and FDA re-report as independent replications.",
      "application_exception": "The 2 bibliographic/regulatory reports are not 2 unique trials. Do not automatically merge other trial families in the full label into the same trial.",
      "criterion": "Link matching design/n/dose in the article and regulatory table without inventing a patient-level crosswalk or 2 independent trials.",
      "basis": "M04 §4.6.1–4.6.2: distinction between studies and reports; cohort/outcome linkage is local application; M04 §4.6.1–4.6.2, M15 §15.3.1: local application — case-specific adaptation for reports and trial family.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Review report–trial–outcome correspondence, distinguishing repeated citations of the same family from unconfirmed detailed links."
    },
    {
      "item_id": "N24",
      "question_type": "Independent replication",
      "question": "Is independent replication of this question verified?",
      "needed": "Unique families, outcomes, funding and authorship for additional eligible trials.",
      "role": "Supplementary; required for replication claims",
      "role_reason": "Needed to avoid automatically promoting multiple label trials or original R1 into an independent-replication count.",
      "application_exception": "Unavailable additional eligible material does not mean 0 studies worldwide or no effect.",
      "criterion": "Link unique studies with the same product/population/measure to independent author and funding information.",
      "basis": "M04 §4.6.1–4.6.2, M15 §15.3.1: local application; M04 §4.6.1–4.6.2: distinction between studies and reports; cohort/outcome linkage is local application; Chamgap’s own independence/attribution condition. The official methodological sections used in this pilot do not guarantee all these details — case-specific adaptation for independent replication.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Compare eligible families, remove duplicate reports and record differences in conditions and unverified independence."
    },
    {
      "item_id": "N25",
      "question_type": "Funding and COI",
      "question": "Are research funding, product provision and author interests verified?",
      "needed": "Complete original article funding, product provision, employment/patents and COI declarations.",
      "role": "Supplementary; required for independence claims",
      "role_reason": "Needed to avoid converting unavailable full text into certainty of manufacturer-only or independent research.",
      "application_exception": "Do not infer specific funding or the magnitude of bias from the NIASPAN product name or regulatory table alone.",
      "criterion": "Link actual full funding/COI declarations while retaining uncertainty about manufacturer-only or independent funding.",
      "basis": "Chamgap’s own independence/attribution condition. The official methodological sections used in this pilot do not guarantee all these details — case-specific adaptation for funding and COI.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Compare original declarations with authors/institutions and study families, recording verified interests separately from uncertainty."
    },
    {
      "item_id": "N26",
      "question_type": "Inconsistent reports",
      "question": "Are the causes of inconsistent reports for other doses/endpoints verified?",
      "needed": "Relevant original publisher-abstract/regulatory-table data, phases/denominators and corrections for 1000 mg LDL, TG and related values.",
      "role": "Required",
      "role_reason": "Needed to avoid erasing related inconsistencies because some values agree or arbitrarily correcting them as rounding.",
      "application_exception": "A different dose alone is not automatically conflicting data. Retain only inconsistencies explicit in the current record; do not invent causes or new values.",
      "criterion": "Retain the agreeing 2000 mg LDL value and mark the causes of actual inconsistencies for other doses/endpoints as unverified.",
      "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3: state separation is locally designed; M04 §4.6.1–4.6.2, M15 §15.3.1: local application — case-specific adaptation for inconsistent reports.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Compare dose, measure, time and denominator for each inconsistent item, distinguishing conflicting reports of the same contrast from values under different conditions."
    },
    {
      "item_id": "N27",
      "question_type": "Extension to clinical events",
      "question": "Does LDL-C change answer whether myocardial infarction or mortality is prevented?",
      "needed": "Direct event studies with the same strategy/population if extending to events or mortality.",
      "role": "Supplementary; required for clinical-event extensions",
      "role_reason": "Needed to avoid automatically converting surrogate improvement into prevention of clinical events.",
      "application_exception": "Do not require an event trial for the narrow LDL-C percentage-change question. This table does not assess event prevention.",
      "criterion": "Separate the lipid-change question from event/mortality questions.",
      "basis": "M03 §3.2.4: locally defined extension boundary — case-specific adaptation for extension to clinical events.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "If an extension is claimed, review event-study populations, formulations, comparators and durations in a separate eligibility table."
    },
    {
      "item_id": "N28",
      "question_type": "Dose and long-term extensions",
      "question": "Does the result answer questions about optimal dose, long-term maintenance or specific subgroups?",
      "needed": "Direct dose comparisons, long-term follow-up and prespecified subgroup/interaction data if extending the claim.",
      "role": "Supplementary; required for the relevant extension",
      "role_reason": "Needed to avoid transferring one key dose/period to optimization or maintenance effects.",
      "application_exception": "The presence of a 1000 mg arm does not establish an optimal dose. Do not require every long-term/subgroup study for the narrow 16-week question.",
      "criterion": "Do not extend the fixed-comparison 16-week result to optimal dose, long-term persistence or effect modification.",
      "basis": "M03 §3.2.1–3.2.4: dose, duration and effect-modification details are locally designed — case-specific adaptation for dose and long-term extensions.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Review direct comparisons, follow-up and interactions separately for extensions outside the original question; do not average supporting arms of the same trial."
    },
    {
      "item_id": "N29",
      "question_type": "Harm collection and denominators",
      "question": "Are arm-specific harm collection, event/person counts and stopping denominators verified for the key trial?",
      "needed": "The key trial’s AE definitions, collection, people/events, stopping, exposure time and arm-specific denominators.",
      "role": "Supplementary; required for harm/safety claims",
      "role_reason": "The presence of efficacy data or regulatory warnings does not establish complete harm counts in the same trial.",
      "application_exception": "Do not use FDA2020 pooled safety data as event rates in this trial or convert unverified harms into harmlessness or AE0.",
      "criterion": "Separate original warnings from actual arm-specific harm counts in the key small trial; do not use pooled data as trial event rates.",
      "basis": "M19 §19.1.2–19.2.4: local application; M19 §19.1.2–19.2.4: detailed distinctions are locally designed; M19 §19.1.2–19.2.4, M04 §4.6.3: local application — case-specific adaptation for harm collection and denominators.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Link arm-specific safety tables/collection procedures to follow-up and check which trials contribute to FDA pooled data."
    },
    {
      "item_id": "N30",
      "question_type": "Harm timing and alternatives",
      "question": "Are temporal order, co-treatment and alternative comparative causes verified for harms in the selected trial?",
      "needed": "Trial AE onset, stopping/recovery, concurrent medication/baseline disease, comparisons and long-term vulnerable-group data.",
      "role": "Supplementary; required for harm causality/scope",
      "role_reason": "Needed to avoid automatically extending label warnings to causal risk estimates or overall safety in the selected trial.",
      "application_exception": "Do not invent rechallenge, recovery, incidence or rare long-term-risk values from a summary without event counts. No H07 independent replicated-harm claim is made in this work.",
      "criterion": "Link warnings to actual timing, comparisons and alternatives in the same population/exposure, without converting a signal to a causal rate.",
      "basis": "M19 §19.1.2–19.2.4: local application; M19 §19.2: design-specific harm questions, with locally designed temporal details; M19 §19.2.2–19.2.4, M03 §3.2.3: local application; M19 §19.2.2–19.2.4: design considerations, with locally designed confounding records; Chamgap’s own interpretive boundary. M19 principles inform this work; no official causality tool was executed — case-specific adaptation for harm timing and alternatives.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Link exposure/event timelines and co-treatment to actual counts and review the possible scope of causal, frequency and long-term extrapolation."
    },
    {
      "item_id": "N31",
      "question_type": "Laboratory interference",
      "question": "Within what scope was reported laboratory interference verified?",
      "needed": "FDA7.6 assay-specific interference conditions and the original trial LDL-C assay/interference observations.",
      "role": "Supplementary; required for interference claims",
      "role_reason": "Needed to avoid extending label interference warnings to invalidation of this trial’s LDL-C effect or interference with all tests.",
      "application_exception": "Do not add test names, mechanisms or frequencies absent from the original inputs or assert that LDL-C interference occurred.",
      "criterion": "Do not convert original assay-specific warnings into actual LDL-C measurement errors or effects on all tests.",
      "basis": "M19 §19.1.2–19.2.4: local application; M19 §19.1.2–19.2.4: detailed distinctions are locally designed; Chamgap’s own interpretive boundary. M19 principles inform this work; no official causality tool was executed; M08 Table 8.2.a, M03 §3.2.4: local application — case-specific adaptation for laboratory interference.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Compare assay-specific conditions in the official document with original measurement methods, separating general warnings from interference observed in the trial."
    },
    {
      "item_id": "N32",
      "question_type": "Material reading",
      "question": "Which material was actually read in this work?",
      "needed": "Current input SHA, material type/URL, historical access locations, individual access dates and global review date.",
      "role": "Required",
      "role_reason": "Needed to avoid converting reading of the retained summary into current reading of FDA PDFs, articles or DOI-linked full texts.",
      "application_exception": "Citations have no individual access dates. Do not infer that the 2026-09-14 review date was an actual access date or automatically inherit report access for the DOI entry.",
      "criterion": "Distinguish original-byte retained summaries, historical access in original citations and current external access not attempted/unread for each material.",
      "basis": "M04 §4.5–4.6: material-collection/selection principles; access/reading separation and the hyperlink contract are locally designed; M04 §4.5, §4.6.3: current-record conversion limits derive from user scope and local design — case-specific adaptation for material reading.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Compare existence, acquisition, reading status and original locations by report, separating blue summary links from unread external full texts."
    },
    {
      "item_id": "N33",
      "question_type": "Verification scope and history",
      "question": "What search, correction and history scope is retained?",
      "needed": "Existing search records, 5 corrections, inputs used and the unpublished/registration verification scope.",
      "role": "Required",
      "role_reason": "Needed to avoid promoting old internal validation/web indexing to a current exhaustive clinical search.",
      "application_exception": "Separate original verification reports, source lists and shared correction records were not opened in this work; S17/S19 without citations are not made into new reports.",
      "criterion": "Distinguish the 2026-09-14 web indexing/existing searches/corrections from this local conversion.",
      "basis": "M04 §4.5, §4.6.3: current-record conversion limits derive from user scope and local design; M04 §4.6.3, M15 §15.3.1–15.3.3: state separation is locally designed; M08 Table 8.2.a, M04 §4.6.3: local application — case-specific adaptation for verification scope and history.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Check the scope actually retained for search logs/corrections and limit uncertainty statements to the relevant sections/dates."
    },
    {
      "item_id": "N34",
      "question_type": "Original assessment and table status",
      "question": "How are original assessments/numbers distinguished from table-review status?",
      "needed": "Original grade/score/axes, calculation records, gaps, corrections and original internal-review metadata.",
      "role": "Required (display boundary)",
      "role_reason": "Needed to avoid interpreting blue verification in the table as a new clinical-efficacy grade, fulfilment percentage or official certification.",
      "application_exception": "Original document-quality A and internal validation are distinct from evidence C/46. Table preparation, another author’s QA, technical/UI checks and publication are also separate statuses.",
      "criterion": "Retain C46, original axes/EX/CX, original caution, nulls and historical arithmetic; table-preparation verification is not efficacy/safety certification.",
      "basis": "M03 §3.1, §3.2.1–3.2.4: question-clarification principles; detailed separation rules are locally designed; M04 §4.5, §4.6.3: current-record conversion limits derive from user scope and local design; M15 §15.3.1–15.3.3: local application; Chamgap’s own interpretive boundary. M19 principles inform this work; no official causality tool was executed — case-specific adaptation for original assessment and table status.",
      "condition_origin": "Locally developed conditions fitted to a known retained case; not blinded or preregistered validation or official clinical certification.",
      "proposed_research": "Compare the complete retained summary with derived tables, separating technical checks from content review of unchanged original values/nulls, inconsistencies and condition states."
    }
  ],
  "language": "en",
  "translation_date": "2026-10-29"
}