{
  "title": "Oral single-active-ingredient pantothenic acid (vitamin B5) supplementation × Reduction in LDL-C concentration in adults with elevated LDL-C",
  "criteria_version": "NGM-v3100-SOLE-ORAL-B5-ELEVATED-LDL-C-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, and distinguish variations of the intervention.",
      "review_level": "Reuse of the preserved methodological principles/version from 1585 and the actual 5 HTML copies; not a new reading of full methodological texts or application of official tools"
    },
    {
      "id": "M04",
      "version": "Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03",
      "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-04",
      "section": "§4.5, §4.6.1–4.6.3, MECIR C42",
      "official_principle": "Distinguish and link studies and reports, and do not omit a study merely because an outcome is unreported.",
      "review_level": "Reuse of the preserved methodological principles/version from 1585 and the actual 5 HTML copies; not a new reading of full methodological texts or application of official tools"
    },
    {
      "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, and review randomization, deviations, missingness, measurement, and selective reporting.",
      "review_level": "Reuse of the preserved methodological principles/version from 1585 and the actual 5 HTML copies; not a new reading of full methodological texts or application of official tools"
    },
    {
      "id": "M15",
      "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08",
      "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-15",
      "section": "§15.2.4, §15.3.1–15.3.3",
      "official_principle": "Distinguish effect estimates, intervals, importance, and applicability. Sample size alone does not determine precision.",
      "review_level": "Reuse of the preserved methodological principles/version from 1585 and the actual 5 HTML copies; not a new reading of full methodological texts or application of official tools"
    },
    {
      "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": "A harm question may require designs, populations, and follow-up different from those for efficacy. Case reports do not establish incidence rates.",
      "review_level": "Reuse of the preserved methodological principles/version from 1585 and the actual 5 HTML copies; not a new reading of full methodological texts or application of official tools"
    }
  ],
  "status_dictionary": {
    "Partly verified": "Some adjacent/bibliographic and historical information verified; gaps remain in direct monotherapy evidence, outcomes, denominators, plans, and access",
    "Unverified": "The selected direct outcome or necessary material could not be verified within the preserved scope; this does not mean 0 studies or no effect",
    "Review incomplete": "Original-material comparison/search was not performed within the permitted scope",
    "Not reported": "A scope-limited status meaning that the item was not stated in the specific material/section read",
    "Inaccessible": "Used only for material for which access was actually attempted and failed. Not assigned to clinical material in this review",
    "Insufficient evidence meeting the conditions": "Used only when evidence is insufficient to answer a condition after relevant studies within the defined scope have been reviewed. Not applied comprehensively in this review",
    "Not applicable": "Extensions to events, optimal dose, persistence, or all populations are not imposed as additional requirements for the selected concentration question; this does not substitute for unverified data",
    "Conflicting information": "When materials that are difficult to reconcile for the same question, time point, and analysis have been compared. Not assigned merely because a review reports different numerical values",
    "Met": "Verification of the stated preservation, boundaries/measures/attribution, and material linkages; not direct B5 LDL-C efficacy, full-text reading, or safety certification"
  },
  "schema_version": "chamgap-public-criteria-1.0",
  "condition_origin": "Chamgap’s own application conditions",
  "requirements": [
    {
      "item_id": "N01",
      "question_type": "Independent claim",
      "question": "Which ingredient, population, and LDL-C comparison?",
      "needed": "Adults with elevated LDL-C, oral B5 monotherapy, comparator with the same background treatment, between-group change in LDL-C",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid combining all lipid-related efficacy claims for the ingredient into a single question.",
      "application_exception": "Pantethine, multicomponent products, acne, and clinical events are separate questions.",
      "criterion": "Link the current original effect wording and inclusion/exclusion boundaries to exact locations.",
      "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed; M03 §3.2.1; detailed population conditions are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to laboratory tests are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare differences in ingredient, population, endpoint, and comparison between the existing question and candidate results for each material."
    },
    {
      "item_id": "N02",
      "question_type": "Molecule and route",
      "question": "Are pantothenic acid and pantethine the same intervention?",
      "needed": "Exact molecule, salt, active ingredient, and route of administration",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid transferring clinical results solely on the basis of a description as a derivative.",
      "application_exception": "Verify the exact salt of calcium pantothenate separately and perform no new mass conversion.",
      "criterion": "Link differences in substance, combination, and route to the original text and explain the limits of direct attribution.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to laboratory tests are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare product composition and chemical-form documents for each result to verify whether the active ingredient is the same."
    },
    {
      "item_id": "N03",
      "question_type": "Product specifications",
      "question": "Are the origin, salt, and formulation of an eligible single-active-ingredient product known?",
      "needed": "Manufacturing origin, brand, exact salt, purity, batch, tablet/capsule, and release type",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid inserting the specifications of another molecule or multicomponent product into those of the directly relevant product.",
      "application_exception": "An oral single-active-ingredient product specified in the question is not an actual product specification.",
      "criterion": "Distinguish verified values for a directly eligible formulation from unverified product items.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to laboratory tests are internally designed",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Verify formulation analysis, batch, and composition materials by linking them to actual comparative trial results."
    },
    {
      "item_id": "N04",
      "question_type": "Dose and frequency",
      "question": "What are the actual dose and total exposure for B5 monotherapy?",
      "needed": "Single-active-ingredient dose, frequency, active amount, dietary/concurrent supplementation, and adherence",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid using the pantethine dose as a pantothenic-acid treatment dose.",
      "application_exception": "The 600/900 mg pantethine doses, nutritional reference values, and examples of high-dose harms are separate records.",
      "criterion": "Verify the directly eligible dose and actual total exposure, leaving unavailable values unfilled.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to laboratory tests are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M03 §3.2.1–3.2.4; details of dose, duration, and effect modification are internally designed",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Collect administration, composition, adherence, and dietary-exposure records by arm to examine actual differences in intervention."
    },
    {
      "item_id": "N05",
      "question_type": "Duration and time points",
      "question": "Have the directly relevant treatment duration and assessment time points been verified?",
      "needed": "Single-active-ingredient administration duration, planned/actual LDL-C time points, and follow-up",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid using 16 weeks for another substance as a verified value for the single-active-ingredient treatment.",
      "application_exception": "Do not arbitrarily specify a universal minimum treatment duration.",
      "criterion": "Distinguish eligible single-active-ingredient durations and time points from the duration of a related trial.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to laboratory tests are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare the plan, actual exposure, and time points in outcome tables to distinguish prespecified endpoints from follow-up."
    },
    {
      "item_id": "N06",
      "question_type": "Population selection",
      "question": "How were adults with elevated LDL-C selected?",
      "needed": "Diagnostic threshold, baseline LDL-C, age, inclusion/exclusion, and setting",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid mistaking the population label in the question for actual recruitment criteria.",
      "application_exception": "Do not transfer the cardiovascular-risk and statin-eligible population of a pantethine trial to the single-active-ingredient population.",
      "criterion": "Explain the actual recruitment/diagnosis in directly eligible studies and what remains unverified.",
      "basis": "M03 §3.2.1; detailed population conditions are internally designed",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Obtain recruitment and baseline tables and exclusion criteria, and compare them with the population in the selected question."
    },
    {
      "item_id": "N07",
      "question_type": "Baseline and concomitant treatment",
      "question": "Can lipid-lowering medications, diet, deficiency, and other supplementation be distinguished?",
      "needed": "Arm-specific lipid-lowering medications, diet, deficiency/nutritional status, and concurrent supplementation",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid using differences in background treatment and correction of deficiency as an additional B5 effect.",
      "application_exception": "If baseline deficiency is unverified, do not establish that deficiency is absent.",
      "criterion": "Link the scope and limitations of baseline/concomitant-treatment verification in eligible single-active-ingredient studies.",
      "basis": "M03 §3.2.1; detailed population conditions are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare baseline nutrition, medications, diet, and records of arm-specific changes with analyses for each outcome."
    },
    {
      "item_id": "N08",
      "question_type": "Comparator and background treatment",
      "question": "What are the placebo or usual care and the actual shared treatment?",
      "needed": "Actual placebo composition, usual care, rescue treatment, and arm-specific changes",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid using the planned comparison as verification of the actual comparator arm.",
      "application_exception": "Do not require all changes in both arms to be identical; examine them in relation to the effect of interest.",
      "criterion": "Distinguish the actual comparison, differences other than the intervention, and their implications for analysis.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to laboratory tests are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Link arm-specific prescriptions, comparator composition, rescue treatment/changes, and analysis plans to verify the scope of contribution."
    },
    {
      "item_id": "N09",
      "question_type": "Measurement method",
      "question": "Were directly measured LDL and formula-calculated LDL distinguished?",
      "needed": "LDL measurement method, specimen/blood collection, calculation formula, and arm-specific procedures",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid establishing that values from different measurement methods represent the same endpoint.",
      "application_exception": "Do not convert other lipid markers or oxidative stability into LDL-C concentration.",
      "criterion": "Explain the actual measurement conditions for eligible LDL-C results and the scope that cannot be verified.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare measurement methods, calculation formulas, blood-collection conditions, and assessment procedures with each outcome table."
    },
    {
      "item_id": "N10",
      "question_type": "Endpoint and units",
      "question": "Are differences in change, endpoint differences, and percentages the same value?",
      "needed": "LDL-C definition, units, baseline/change/endpoint values, and between-group/within-group distinctions",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid converting within-group percentages into placebo-adjusted concentration differences.",
      "application_exception": "Perform no new conversion between mg/dL and mmol/L.",
      "criterion": "Separate the selected between-group change in concentration from the different measures in related reports.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Link outcome definitions, analyses, units, and time points to the original tables and protocol, preserving each separately."
    },
    {
      "item_id": "N11",
      "question_type": "Effect of interest",
      "question": "What intervention effect does an eligible analysis estimate?",
      "needed": "Between-group/within-group, change/endpoint, adjustment, ITT/PP, and analysis population",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid transferring different effect definitions into the same estimate.",
      "application_exception": "Do not assume ITT or an adjusted effect if no record is available.",
      "criterion": "Explain how the actual effect definition in directly eligible results agrees with or differs from the question.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare the analysis plan with actual outcome tables to verify the effect of interest, adjustment, and denominators."
    },
    {
      "item_id": "N12",
      "question_type": "Effect and interval",
      "question": "Are the directly relevant LDL-C effect, CI, and P value known?",
      "needed": "Eligible between-group effect, uncertainty interval, P value, and units",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid converting an unverified result into an effect of 0 or nonsignificance.",
      "application_exception": "Do not reconstruct pantethine results, other biomarkers, or graphs as a directly relevant effect.",
      "criterion": "Distinguish the unverified direct-effect fields from related results.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M15 §15.3.1–15.3.3; internal application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Review estimates, intervals, variance, and denominators in eligible outcome tables by attributing them to the actual analyses."
    },
    {
      "item_id": "N13",
      "question_type": "Directly relevant denominators",
      "question": "How many participants were allocated, measured, analyzed, and completed, respectively?",
      "needed": "Arm-specific allocation/analysis/completion for the single-active-ingredient treatment, missing data, and outcome-specific denominators",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid using related sample sizes as directly relevant LDL-C analysis denominators.",
      "application_exception": "32 allocated and 24 completed are denominators from the pantethine trial.",
      "criterion": "Distinguish directly relevant outcome-specific denominators from what remains unverified.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M15 §15.3.1–15.3.3; internal application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare participant flow, reasons for missing data, and outcome-specific analysis tables to verify denominators."
    },
    {
      "item_id": "N14",
      "question_type": "Allocation and assessment",
      "question": "Are the design, concealment, and blinding of the monotherapy comparison known?",
      "needed": "Actual design, allocation/concealment, baseline balance, and assessment procedures",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid using a triple-blind label from a related study as a direct B5 bias assessment.",
      "application_exception": "Do not mark crossover or cluster designs as not applicable when the design is unverified.",
      "criterion": "Link the actual design/assessment information and limitations of the directly selected results.",
      "basis": "M08 §8.1–8.2.3; internal application; M08 Table 8.2.a, M03 §3.2.4; internal application; M03 §3.2.1; detailed population conditions are internally designed",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Obtain monotherapy methods, registration, and baseline/assessment materials and review them at the outcome level."
    },
    {
      "item_id": "N15",
      "question_type": "Adherence and discontinuation",
      "question": "Are adherence, rescue treatment, analysis populations, and missing-data handling known?",
      "needed": "Actual intake, discontinuation, arm-specific changes, ITT/PP, and missing-data handling",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid mixing the effect of assignment with before-and-after effects among adherent participants/completers.",
      "application_exception": "Do not arbitrarily fill in analysis methods absent from the original text.",
      "criterion": "Distinguish directly eligible information on adherence, withdrawals, and analysis from what remains unverified.",
      "basis": "M03 §3.2.3, M08 §8.2.2–8.2.3; own application; M08 §8.2.2, M15 §15.3.1; own application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations by study design are this project's own design",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare the analysis plan, administration records, and participant flow against the results tables to examine their impact."
    },
    {
      "item_id": "N16",
      "question_type": "Precision and importance",
      "question": "What magnitudes of difference does the reported interval allow?",
      "needed": "Direct effect/CI, variance, and a justified important difference",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid declaring sufficiency based only on sample size, statistical significance, or the number of trials.",
      "application_exception": "Do not arbitrarily adopt a common minimum sample size, duration, or MCID.",
      "criterion": "Explain the relationship between the reported interval and the importance criterion, or why it cannot be interpreted.",
      "basis": "M15 §15.3.1–15.3.3; own application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations by study design are this project's own design",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Obtain the basis for importance appropriate to the endpoint/population and the actual reported interval separately, and compare them."
    },
    {
      "item_id": "N17",
      "question_type": "Positive adjacent results",
      "question": "What produced the LDL-C improvement in Evans?",
      "needed": "Actual ingredients, within-arm changes, time points, and original tables from the pantethine trial",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to preserve attribution to a different molecule without concealing favorable results.",
      "application_exception": "Do not calculate a new between-group effect from the two changes from baseline.",
      "criterion": "Explain the measure, duration, and substance in the positive report together with the reason for its direct ineligibility.",
      "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is this project's own design; M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for tests are this project's own design; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are this project's own design; M04 §4.6.1–4.6.2, M15 §15.3.1; own application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare the original LDL-C tables against the product/analysis documents to verify the scope of the reported values."
    },
    {
      "item_id": "N18",
      "question_type": "Different P tests",
      "question": "Are P=0.006 and P=0.010 the same comparison?",
      "needed": "Concentration comparison, percentage-change comparison, actual analysis, and time points",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid merging distinct reported tests into one.",
      "application_exception": "Do not convert a P value into an effect size or CI.",
      "criterion": "Preserve the P values for the comparisons distinguished in the original text, their attribution, and the unverified aspects.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are this project's own design; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is this project's own design; M08 §8.2.2, M15 §15.3.1; own application; M15 §15.3.1–15.3.3; own application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare the concentration/percentage results tables and the analysis plan to verify the definition and denominator of each test."
    },
    {
      "item_id": "N19",
      "question_type": "Adjacent-study denominators",
      "question": "What do 32 allocated and 24 completed mean?",
      "needed": "Evans allocation, completion, analyses by arm/endpoint, and reasons for dropout",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid treating the overall allocation/completion counts as the same analysis denominator.",
      "application_exception": "Do not calculate new arm-specific dropout counts or rates from the difference.",
      "criterion": "Preserve the related trial's original denominators and explain the unverified aspects of the direct/arm-specific analyses.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations by study design are this project's own design; M08 §8.2.2, M15 §15.3.1; own application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Link Evans's participant flow with the outcome-specific analysis tables to review the denominators."
    },
    {
      "item_id": "N20",
      "question_type": "Reports of the same trial",
      "question": "Are PMC and PubMed independent replication trials?",
      "needed": "S101/S102 DOI, PMID, trial, and outcome linkage",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid counting reports as unique trials.",
      "application_exception": "Do not automatically establish that other references concern the same cohort or independent trials.",
      "criterion": "Distinguish verified links between reports of the same study from unresolved families.",
      "basis": "Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an own application; M04 §4.6.1–4.6.2, M15 §15.3.1; own application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Track registration, recruitment, participant, and trial identifiers across reports to check for overlap."
    },
    {
      "item_id": "N21",
      "question_type": "Funding and independence",
      "question": "Were Evans's funding and independent replication verified?",
      "needed": "Reported funding, product/author relationships, institutions, and family linkage",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid turning original funding reports into independent funding or absence of bias.",
      "application_exception": "Do not automatically exclude results because funding was provided.",
      "criterion": "Explain the verified funding and the scope of unverified disclosures/independence.",
      "basis": "Chamgap's own conditions for independence and attribution. The official methods sections used in this pilot do not guarantee all of these detailed items; distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an own application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Separately compare paper disclosures, product provision, author/institutional relationships, and study families."
    },
    {
      "item_id": "N22",
      "question_type": "Nonhuman mechanisms",
      "question": "Do mouse/adipocyte results answer the question about human LDL-C?",
      "needed": "Species, sex, experimental system, measured endpoints, and whether a human comparison exists",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid transferring mechanistic observations to a human lipid effect of a single active ingredient.",
      "application_exception": "Preserve nonhuman studies within their scope without deleting them.",
      "criterion": "Explain the difference between the actual nonhuman subjects and the direct human question.",
      "basis": "M03 §3.2.1; detailed population conditions are this project's own design; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are this project's own design; M03 §3.2.4; own boundary on extensions",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare, for each material, the differences between the experimental endpoints and the human intervention, population, and LDL-C estimand."
    },
    {
      "item_id": "N23",
      "question_type": "Possible preprint",
      "question": "Are S103 and S104 the same study?",
      "needed": "Relationships among the preprint/paper, authors, experiments, and versions",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid summing a possibly related preprint as an independent replication.",
      "application_exception": "Do not establish that studies are identical solely from similar titles.",
      "criterion": "Distinguish the preserved possible relationship, verified identifiers, and remaining gaps.",
      "basis": "Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an own application; data collection/selection principles in M04 §4.5–4.6; separation of access and reading and the hyperlink contract are this project's own design; M04 §4.6.1–4.6.2, M15 §15.3.1; own application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Check correspondence among versions, authors, experiments, and data, and record whether they belong to the same or different families."
    },
    {
      "item_id": "N24",
      "question_type": "Combination-product protocol",
      "question": "Is the NCT03444155 protocol a single-active-ingredient B5 result?",
      "needed": "Protocol version, combination composition, comparator, administration plan, and actual results",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to distinguish plans from results and contributions within a combination.",
      "application_exception": "A record of protocol access does not verify actual allocation or results.",
      "criterion": "Explain the attribution of the actual combination protocol and the unverified single-active-ingredient results.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for tests are this project's own design; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are this project's own design; M03 §3.2.3, M08 §8.2.2–8.2.3; own application; M08 Table 8.2.a, M04 §4.6.3; own application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare the planned composition, results/registration, and analysis plan to examine actual conduct and the contribution of the single ingredient."
    },
    {
      "item_id": "N25",
      "question_type": "Registration and selective reporting",
      "question": "Were the planned endpoint and reporting for the selected LDL-C outcome compared?",
      "needed": "Directly eligible registration, protocol, SAP, and actual reporting/changes",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to identify the material required to check whether only favorable analyses were selected.",
      "application_exception": "Do not turn failure to acquire material into confirmation of nonregistration or selective reporting.",
      "criterion": "Indicate the actual scope of plan/report comparison for the direct comparison and the aspects not compared.",
      "basis": "Data collection/selection principles in M04 §4.5–4.6; separation of access and reading and the hyperlink contract are this project's own design; M04 §4.5, §4.6.3; limitations of the current material conversion follow the user's scope and this project's own design; M08 Table 8.2.a, M04 §4.6.3; own application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Review the direct trial by linking registration, plans, reporting time points/analyses, and reasons for changes."
    },
    {
      "item_id": "N26",
      "question_type": "Earlier pantethine references",
      "question": "Are the three references from the previous 366 direct B5 replications?",
      "needed": "Gaddi/Rumberger original trials, McRae review, molecules, and included study families",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid summing earlier references, reviews, and trials as independent single-active-ingredient B5 replications.",
      "application_exception": "Do not carry over the previous C and 52 points to the new question.",
      "criterion": "Distinguish each material type, molecule, and unverified results/families.",
      "basis": "Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an own application; data collection/selection principles in M04 §4.5–4.6; separation of access and reading and the hyperlink contract are this project's own design; M04 §4.6.1–4.6.2, M15 §15.3.1; own application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare the identities of the original trials, review inclusion tables, and related reports to check overlap and population differences."
    },
    {
      "item_id": "N27",
      "question_type": "Earlier different questions",
      "question": "Are skin 028 and acne 3099 LDL-C results?",
      "needed": "Identity, endpoints, and linkage of the earlier composite skin/hair and acne questions",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid merging different outcomes for the same ingredient into this efficacy question.",
      "application_exception": "Reading the reference records in 3100 differs from directly reading the earlier original files.",
      "criterion": "Preserve the differences between the original related questions and the selected LDL-C endpoint, and the reading gaps.",
      "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are this project's own design; data collection/selection principles in M04 §4.5–4.6; separation of access and reading and the hyperlink contract are this project's own design; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are this project's own design",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Compare differences in the identities, endpoints, and composition of the related original texts to the extent needed."
    },
    {
      "item_id": "N28",
      "question_type": "Mixed-product and search leads",
      "question": "What is the scope of the S107/S108/S109 materials?",
      "needed": "Article identifiers, product composition, concentration/oxidative stability, and guideline full texts",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid turning search titles, access failures, and domain addresses into direct clinical results.",
      "application_exception": "Do not count inaccessible materials as negative trials.",
      "criterion": "Explain each lead's material type, different question, and unverified results.",
      "basis": "Data collection/selection principles in M04 §4.5–4.6; separation of access and reading and the hyperlink contract are this project's own design; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are this project's own design; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is this project's own design; M04 §4.5, §4.6.3; limitations of the current material conversion follow the user's scope and this project's own design",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Verify article identity, product/endpoints, and original text to review eligibility for the direct question and the level of results."
    },
    {
      "item_id": "N29",
      "question_type": "Scope of contrary findings and absence",
      "question": "Does an unverified direct result mean an effect of 0 or worldwide absence?",
      "needed": "Verified direct/adjacent and positive/other results, and search scope/failures",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid extending the finding to no effect, refutation, or absence of all studies worldwide.",
      "application_exception": "Do not turn access failures and incomplete searching into negative studies or 0 studies.",
      "criterion": "Explain attribution of all verified results and the limited scope of unverified direct evidence.",
      "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is this project's own design; M04 §4.5, §4.6.3; limitations of the current material conversion follow the user's scope and this project's own design; M04 §4.6.1–4.6.2, M15 §15.3.1; own application",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "In an authorized update, recompare search records, missing materials, and the reasons for each eligibility decision."
    },
    {
      "item_id": "N30",
      "question_type": "Materials and reading",
      "question": "Were current summaries distinguished from historical full-text access?",
      "needed": "Publication, attempted/successful access, acquisition, reading, and actual dates and locations for each material",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid turning historical access_level into original-paper reading in this review.",
      "application_exception": "Do not label unattempted access as failed access or infer access dates from the overall review date.",
      "criterion": "Link the preserved locations actually read in the current review with each referenced material's unread status/historical record.",
      "basis": "Data collection/selection principles in M04 §4.5–4.6; separation of access and reading and the hyperlink contract are this project's own design; M04 §4.5, §4.6.3; limitations of the current material conversion follow the user's scope and this project's own design",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Record the original identity, access/acquisition, actual locations read, and dates separately for each material."
    },
    {
      "item_id": "N31",
      "question_type": "Preservation of the original judgment",
      "question": "Are the original grade, score, and axes new condition statuses?",
      "needed": "Original ?, empty values, B/S, unscored subsequent axes/strength, and gate/original calculation",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid elevating an earlier score or an absence gate into a new judgment.",
      "application_exception": "The conditional record of the original C cap is also not an application or a new calculation in this review.",
      "criterion": "Preserve the original judgment values as quotations and distinguish them from conditions being met in the new table.",
      "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are this project's own design; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is this project's own design; M04 §4.5, §4.6.3; limitations of the current material conversion follow the user's scope and this project's own design",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "In a separately authorized update, record the original calculation inputs/rules and reasons for changes, while preserving the original and its versions."
    },
    {
      "item_id": "N32",
      "question_type": "Extension to clinical events",
      "question": "Does an LDL-C difference answer questions about cardiovascular events or medication replacement?",
      "needed": "Boundary between the selected laboratory result and questions about events/treatment replacement",
      "role": "Supplementary (boundary for extension to clinical events)",
      "role_reason": "Needed to prevent automatic extension from a surrogate marker to prevention of clinical events.",
      "application_exception": "An event trial is not imposed as an additional requirement for the LDL-C concentration question itself.",
      "criterion": "Distinguish the original question from a separate extension to clinical events.",
      "basis": "M03 §3.2.4; extension boundary specified by the author",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Review direct clinical comparisons for a separate question that makes a claim about events or treatment replacement."
    },
    {
      "item_id": "N33",
      "question_type": "Extensions to dose and persistence",
      "question": "Does the evidence answer questions about optimal dose, persistence after discontinuation, and all subgroups?",
      "needed": "Direct dose comparisons, discontinuation/long-term follow-up, and prespecified subgroups/interactions",
      "role": "Supplementary (extensions to dose, persistence, and populations)",
      "role_reason": "Needed to prevent extension of the narrow concentration question to optimal dose, persistence, or efficacy in all populations.",
      "application_exception": "Extension studies are not imposed as requirements for the current question as a whole.",
      "criterion": "Separately distinguish extensions to dose/persistence and populations that are absent from direct comparisons.",
      "basis": "M03 §3.2.1–3.2.4; details on dose, persistence, and effect modification use the author's own design",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Link comparisons and outcomes appropriate to separate dose, follow-up, and effect-modification questions to the planned/actual analyses."
    },
    {
      "item_id": "N34",
      "question_type": "General harms and nutrition",
      "question": "Do high-dose harms and nutritional reference values establish a lipid-treatment dose?",
      "needed": "Harms involving the same ingredient, exposure, denominator/duration, collection, and nutritional reference values",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to prevent general descriptions of harms from being converted into incidence rates, treatment doses, or confirmation of overall safety.",
      "application_exception": "The 10 g/day example is not a toxicity threshold/recommendation, and 5 mg/day is the adult adequate intake.",
      "criterion": "Distinguish the original harm/nutrition descriptions from gaps in safety evidence from direct comparisons.",
      "basis": "M19 §19.1.2–19.2.4; the author's own application; M19 §19.1.2–19.2.4; detailed distinctions use the author's own design; Chamgap's own interpretive boundary. The principles of M19 are referenced; this is not an application of a formal causality tool",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Separately verify harm collection matched to the exposure, arm-specific events/discontinuations, and denominator/duration data."
    },
    {
      "item_id": "N35",
      "question_type": "Long-term use and vulnerable populations",
      "question": "Has safety been verified for long-term high-dose use, concomitant use, and vulnerable populations?",
      "needed": "Long-term use for LDL-C, pregnancy/lactation, children, liver/kidney disease, and concomitant use",
      "role": "Supplementary (extension to long-term/concomitant-use safety)",
      "role_reason": "Needed to prevent limited general records from being extended to safety in all populations/combinations.",
      "application_exception": "No known important interactions does not mean that all interactions have been excluded.",
      "criterion": "Indicate the limits of direct safety evidence for the selected purpose and gaps in populations/durations.",
      "basis": "Design considerations in M19 §19.2.2–19.2.4; detailed confounding records use the author's own design; M19 §19.1.2–19.2.4; the author's own application; Chamgap's own interpretive boundary. The principles of M19 are referenced; this is not an application of a formal causality tool",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "Review studies of harms from long-term use, use in special populations, and concomitant use with matching exposure/baseline risk and appropriate collection methods."
    },
    {
      "item_id": "N36",
      "question_type": "Reference date and updates",
      "question": "What can change, as of which date and within which scope?",
      "needed": "Original evidence/review dates, actual current review, search scope, and new data/corrections/retractions",
      "role": "Required (selected B5 monotherapy and LDL-C comparison)",
      "role_reason": "Needed to avoid overstating this conversion as a current comprehensive search, publication, or independent clinical certification.",
      "application_exception": "first_published_at is an editorial reference date, not proof of actual server publication.",
      "criterion": "Separate the original dates and review/access levels from activities not currently performed and the conditions for updates.",
      "basis": "M04 §4.5, §4.6.3; the limits of the current data conversion follow the user's scope and the author's own design; data collection/selection principles in M04 §4.5–4.6; the separation of access from reading and the hyperlink contract use the author's own design; M04 §4.6.3, M15 §15.3.1–15.3.3; status distinctions use the author's own design",
      "condition_origin": "Individual development conditions designed with knowledge of all retained 3100 material; not blinded, clinically preregistered, or independently certified",
      "proposed_research": "In a separately authorized update, preserve the identity of new material, its full original text, and the before/after values, and review the linked conditions again."
    }
  ],
  "language": "en",
  "translation_date": "2026-11-02"
}