{
  "title": "Oral supplemental or medicinal vitamin B6 exposure × risk of new or worsened clinical sensory neuropathy",
  "criteria_version": "NGM-v3098-ORAL-B6-CLINICAL-SENSORY-NEUROPATHY-HARM-1.1",
  "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 document the question, eligibility criteria, and reasons for changes, and distinguish intervention variants.",
      "review_level": "Historical reuse of methodology materials preserved in 1585: the verified original-byte/SHA copy of HTML5 and the principles. This is not new reading of the full methodology or implementation/certification of an official method."
    },
    {
      "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 exclude a study solely because outcomes are unreported.",
      "review_level": "Historical reuse of methodology materials preserved in 1585: the verified original-byte/SHA copy of HTML5 and the principles. This is not new reading of the full methodology or implementation/certification of an official method."
    },
    {
      "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, missing data, measurement, and selective reporting.",
      "review_level": "Historical reuse of methodology materials preserved in 1585: the verified original-byte/SHA copy of HTML5 and the principles. This is not new reading of the full methodology or implementation/certification of an official method."
    },
    {
      "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": "Historical reuse of methodology materials preserved in 1585: the verified original-byte/SHA copy of HTML5 and the principles. This is not new reading of the full methodology or implementation/certification of an official method."
    },
    {
      "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 those for efficacy. Case reports do not establish incidence.",
      "review_level": "Historical reuse of methodology materials preserved in 1585: the verified original-byte/SHA copy of HTML5 and the principles. This is not new reading of the full methodology or implementation/certification of an official method."
    }
  ],
  "status_dictionary": {
    "Met": "The relevant narrow conditions for identity/attribution, original values/boundaries, and reading records are met. This is not a new confirmation of clinical causality, efficacy, absence of risk, or external full texts.",
    "Partly verified": "Relevant preserved observations exist, but some aspects of actual exposure/events, denominators, methods/attribution could not be established.",
    "Unverified": "Not established within the archived materials and the scope verified at that time. This does not mean 0 risk, absence of research worldwide, or access failure in this review.",
    "Conflicting information": "Inconsistent preserved descriptions of the same clinical fact remain. Success in recording and preserving the conflict is distinguished from actual consistent verification.",
    "Not applicable": "Limited to material roles excluded by the question's boundaries. It is not a substitute for unverified/unread/no risk.",
    "Not reported": "Explicitly unreported within the actual preserved manuscript/historical verification scope. This is not extended to the entirety of full texts unread in this review.",
    "Inaccessible": "Limited to actual access failure in this review; the absence of external access attempts in this case is not upgraded to a past failure.",
    "Review incomplete": "Limited to the lack of current external comparison. It does not mean that the actually completed review of local archived summaries/individual models is incomplete."
  },
  "schema_version": "chamgap-public-criteria-1.0",
  "condition_origin": "Chamgap’s own application conditions",
  "requirements": [
    {
      "item_id": "N01",
      "question_type": "Safety contract",
      "question": "Were the original safety-only designation and the contract that efficacy is not applicable preserved?",
      "needed": "Original safety designation, assessment contract, and document-quality metadata",
      "role": "Required",
      "role_reason": "Required to avoid mixing the original warning for the harm question with the meanings of efficacy/document quality.",
      "application_exception": "The original grade ?, empty score value, document quality B, and empty axis_notes are not converted into new efficacy/risk scores.",
      "criterion": "Preserve the links between safety_only true, efficacy not_applicable, framework false, and the original values/absences, without assigning an efficacy badge or total score.",
      "basis": "C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed / C09: M04 §4.5, §4.6.3; limitations on the current material conversion reflect the user-defined scope and internal design / H09: Chamgap's own interpretation boundaries. M19 principles are referenced; no formal causality tool was applied / E10: M19 §19.1.2–19.2.4; internal application. Rationale for application to this case: required to avoid mixing the original warning for the harm question with the meanings of efficacy/document quality. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare the display fields with the technical preservation of the original safety/non-efficacy contract."
    },
    {
      "item_id": "N02",
      "question_type": "Claim boundaries",
      "question": "Was the separate question of oral B6 and new or worsened clinical sensory neuropathy fixed?",
      "needed": "Original claim, population/exposure, route, and endpoint boundaries",
      "role": "Required",
      "role_reason": "Required to distinguish the harm claim from questions about efficacy for treating pre-existing neuropathy or changes in test results.",
      "application_exception": "The scope is not extended to food/parenteral exposure, animals, changes in test values alone, or all neuropathy from other causes.",
      "criterion": "Link the original claim to oral supplement/medicine exposure and clinical new-onset/worsening endpoints, and specify the exclusions.",
      "basis": "C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to testing are internally designed / H01: M19 §19.1.2–19.2.4; detailed distinctions are internally designed / H09: Chamgap's own interpretation boundaries. M19 principles are referenced; no formal causality tool was applied. Rationale for application to this case: required to distinguish the harm claim from questions about efficacy for treating pre-existing neuropathy or changes in test results. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare the roles of material on other routes, treatment of pre-existing disease, and changes in test results against the eligibility boundaries."
    },
    {
      "item_id": "N03",
      "question_type": "Vitamer identity",
      "question": "Are the B6 vitamer, salt, and formulation identities established for each source?",
      "needed": "Original formulation composition, vitamer/salt, and product description",
      "role": "Required",
      "role_reason": "Required to avoid combining different exposures, such as pyridoxine, its hydrochloride, and PLP/P5P, as having the same toxic potency.",
      "application_exception": "Material reporting only pyridoxine is not filled in as the hydrochloride, and absence of risk for PLP is not inferred.",
      "criterion": "Verify the substance and salt actually reported in each source, and leave detailed identity unverified where it is unavailable.",
      "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to testing are internally designed / H05: Design considerations in M19 §19.2.2–19.2.4; detailed recording of confounding is internally designed. Rationale for application to this case: required to avoid combining different exposures, such as pyridoxine, its hydrochloride, and PLP/P5P, as having the same toxic potency. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare the reported substance and actual formulation composition by vitamer."
    },
    {
      "item_id": "N04",
      "question_type": "Product and actual exposure",
      "question": "Are the brand, batch, measured content, and actual dose taken verified?",
      "needed": "Manufacturing/labeling, batch, measured content, and dosing frequency/adherence records",
      "role": "Required",
      "role_reason": "Required to avoid generalizing a nominal administered dose into actual intake or risk for the entire product.",
      "application_exception": "The labeled tablet/capsule amount is not treated as verification of purity, batch/release, dosing frequency, or adherence.",
      "criterion": "Verify the exact product, ingredients/release, measured content, and actual dosing frequency/adherence, and identify the remaining gaps.",
      "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application / H05: Design considerations in M19 §19.2.2–19.2.4; detailed recording of confounding is internally designed. Rationale for application to this case: required to avoid generalizing a nominal administered dose into actual intake or risk for the entire product. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review whether product information agrees with individual intake records."
    },
    {
      "item_id": "N05",
      "question_type": "Multiple products and units",
      "question": "Can content per tablet be distinguished from actual total daily intake across multiple products?",
      "needed": "Product-specific content units, dosing frequency/number taken, and concurrent-exposure table",
      "role": "Required",
      "role_reason": "Required to avoid converting Lareb's per-tablet content or reports involving multiple products into a daily dose/risk threshold.",
      "application_exception": "1.4–100 mg is a per-tablet amount, and the TGA's 9 reports involving multiple products are not an independent group with verified total daily intake.",
      "criterion": "Link content units, number of products, dosing frequency, and background intake, without calculating totals that have not been verified.",
      "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application / H04: M19 §19.1.2–19.2.4; internal application / H05: Design considerations in M19 §19.2.2–19.2.4; detailed recording of confounding is internally designed. Rationale for application to this case: required to avoid converting Lareb's per-tablet content or reports involving multiple products into a daily dose/risk threshold. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare the data units for per-tablet content, per-product content, and total daily intake."
    },
    {
      "item_id": "N06",
      "question_type": "Exposure route",
      "question": "Was oral exposure from supplements/medicines separated from other routes/foods?",
      "needed": "Original route, exposure source, and applicability of related material",
      "role": "Required",
      "role_reason": "Required to avoid transferring human incidence after oral exposure across routes and exposure sources.",
      "application_exception": "Ordinary/fortified foods, parenteral dosing, and animal dosing are not evidence of identical risk for exposure to these formulations.",
      "criterion": "Preserve the original exposure strata for oral supplements/medicines and prevent direct extrapolation from other routes.",
      "basis": "C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to testing are internally designed / H09: Chamgap's own interpretation boundaries. M19 principles are referenced; no formal causality tool was applied. Rationale for application to this case: required to avoid transferring human incidence after oral exposure across routes and exposure sources. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare directness/exclusions according to the original route and exposure stratum."
    },
    {
      "item_id": "N07",
      "question_type": "Population and baseline status",
      "question": "Are the population, pre-exposure neuropathy, and underlying diseases verified for each source?",
      "needed": "Table of inclusion/exclusion, baseline symptoms, examination/disease, renal/hepatic status, and medications",
      "role": "Required",
      "role_reason": "Required to avoid combining healthy volunteers, people with existing CIAP, TB/HIV, and older adults into the same population for new-onset events.",
      "application_exception": "The category of predominantly adults is not converted into normal individual baseline status or safety for special populations.",
      "criterion": "Link the study-specific population, baseline neuropathy, renal/hepatic status, medications, and selection status, and explicitly identify omissions.",
      "basis": "C04: M03 §3.2.1; detailed population conditions are internally designed / H05: Design considerations in M19 §19.2.2–19.2.4; detailed recording of confounding is internally designed / H08: M19 §19.1.2–19.2.4; internal application. Rationale for application to this case: required to avoid combining healthy volunteers, people with existing CIAP, TB/HIV, and older adults into the same population for new-onset events. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review applicability limitations related to baseline risk and population selection."
    },
    {
      "item_id": "N08",
      "question_type": "Clinical event definition",
      "question": "Was clinical sensory neuropathy confirmed/ascertained separately from test markers?",
      "needed": "Original diagnostic criteria, symptoms/examination, QST/conduction, and detection/blinding procedures",
      "role": "Required",
      "role_reason": "Required to avoid substituting changes in PLP/QST/conduction or high blood B6 values for clinical occurrence.",
      "application_exception": "Participants with changes in test results alone and no clinical symptoms are not included as clinical events.",
      "criterion": "Verify symptoms, signs/examination, and confirmation/ascertainment procedures, and separate changes in markers alone from clinical events.",
      "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed / E03: M08 Table 8.2.a, M03 §3.2.4; internal application / E09: M03 §3.2.4; internally defined extension boundaries / H01: M19 §19.1.2–19.2.4; detailed distinctions are internally designed. Rationale for application to this case: required to avoid substituting changes in PLP/QST/conduction or high blood B6 values for clinical occurrence. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare clinical event definitions with differences in measurement/detection of test markers."
    },
    {
      "item_id": "N09",
      "question_type": "Distinguishing new onset from worsening",
      "question": "Can new onset and worsening of pre-existing symptoms be distinguished separately?",
      "needed": "Table of baseline symptoms, event counts for new onset/worsening, populations at risk, and timing",
      "role": "Required",
      "role_reason": "Required to avoid converting results for a mixed endpoint into a single incidence rate of new toxicity.",
      "application_exception": "The mixture of new onset/worsening in the TB cohort or incomplete classification in spontaneous reports is not filled in as separately available values.",
      "criterion": "Verify pre-exposure symptoms and events, denominators, and timing for new onset/worsening, and leave mixed outcomes as mixed.",
      "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed / H01: M19 §19.1.2–19.2.4; detailed distinctions are internally designed / H04: M19 §19.1.2–19.2.4; internal application. Rationale for application to this case: required to avoid converting results for a mixed endpoint into a single incidence rate of new toxicity. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Trace pre-existing disease and the classification of events before and after exposure."
    },
    {
      "item_id": "N10",
      "question_type": "High-dose exposure",
      "question": "Were Berger's reported doses separated from observations of onset and after withdrawal?",
      "needed": "Original table of dosing/onset and follow-up after withdrawal",
      "role": "Required",
      "role_reason": "Required to avoid extending temporal relationships at high doses to low doses generally/all users.",
      "application_exception": "1 or 3 g/day is not converted into a general recommended dose, minimum risk dose, or individual actual cumulative exposure.",
      "criterion": "Attribute the 5 volunteers, reported pyridoxine doses of 1 or 3 g/day, earlier onset, and worsening for 2–3 weeks after withdrawal to their original locations.",
      "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed / H02: Design-specific harm questions in M19 §19.2; temporal-relationship details are internally designed. Rationale for application to this case: required to avoid extending temporal relationships at high doses to low doses generally/all users. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare dose, time to onset, and the course after exposure withdrawal separately."
    },
    {
      "item_id": "N11",
      "question_type": "Conflict in the clinical numerator",
      "question": "Is Berger's actual number of clinical cases consistently verified across sources?",
      "needed": "Correspondence between the original abstract, individual clinical symptom/test table, and EFSA extraction",
      "role": "Required",
      "role_reason": "Required to avoid automatically interpreting the denominator of 5 volunteers as 5/5 clinical occurrence.",
      "application_exception": "Distinguish successful recording of the conflict as it stands from a status in which the clinical numerator has been consistently verified.",
      "criterion": "Compare symptom/test criteria and clinical numerators in the original abstract and EFSA's individual-participant extraction. If disagreement remains, do not treat the numerator as established or claim 100% occurrence.",
      "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed / H01: M19 §19.1.2–19.2.4; detailed distinctions are internally designed / H04: M19 §19.1.2–19.2.4; internal application. Rationale for application to this case: required to avoid automatically interpreting the denominator of 5 volunteers as 5/5 clinical occurrence. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review correspondence of participants/clinical criteria across sources and the disagreement in numerators."
    },
    {
      "item_id": "N12",
      "question_type": "Actual comparator",
      "question": "Were the uncontrolled design of the high-dose experiment and the boundaries of comparative risk preserved?",
      "needed": "Original design, comparator/allocation, and exposure table",
      "role": "Required",
      "role_reason": "Required to avoid converting the temporal relationship of prospective exposure into a randomized comparison with no exposure or a population risk rate.",
      "application_exception": "Observations at the alternative doses 1 or 3 g are not treated as an RCT effect with an unexposed control.",
      "criterion": "Explicitly identify the uncontrolled prospective high-dose design and distinguish it from estimation of population incidence/RR.",
      "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation to testing are internally designed / E01: M08 §8.1–8.2.3; internal application / H03: M19 §19.2.2–19.2.4, M03 §3.2.3; internal application. Rationale for application to this case: required to avoid converting the temporal relationship of prospective exposure into a randomized comparison with no exposure or a population risk rate. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review the scope of causal/risk interpretation permitted by the design and actual comparison conditions."
    },
    {
      "item_id": "N13",
      "question_type": "Recovery and rechallenge",
      "question": "Are recovery/worsening after withdrawal and the actual course on rechallenge verified?",
      "needed": "Original individual event records for withdrawal, follow-up/function, and rechallenge",
      "role": "Required",
      "role_reason": "Required to avoid extending some improvement into complete recovery for everyone or confirmation through rechallenge.",
      "application_exception": "Coasting, persistent disability, and cases of recovery after withdrawal are not converted into a guarantee of individual recovery or a probability of permanent damage.",
      "criterion": "Verify withdrawal/course, completeness of recovery, and rechallenge for each individual, and retain the areas with insufficient information.",
      "basis": "H02: Design-specific harm questions in M19 §19.2; temporal-relationship details are internally designed / H08: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretation boundaries. M19 principles are referenced; no formal causality tool was applied. Rationale for application to this case: required to avoid extending some improvement into complete recovery for everyone or confirmation through rechallenge. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare onset and changes after withdrawal with alternative causes/completeness of follow-up."
    },
    {
      "item_id": "N14",
      "question_type": "Overlap within a reporting series",
      "question": "Are the independence and overlap relationships of Lareb reports verified?",
      "needed": "Original report identifiers, collection period, and overlap/re-citation correspondence table",
      "role": "Required",
      "role_reason": "Required to avoid adding the 2018/2025/EFSA interim counts as independent reports/trials.",
      "application_exception": "90 and 224 overlap within the same reporting series, and official re-citations are not separate replications in humans.",
      "criterion": "Link the series, collection period, and overlap relationships, and do not sum counts when individual overlap/independent events are unverified.",
      "basis": "C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / H07: M04 §4.6.1–4.6.2; adaptation to harm material is internally designed. Rationale for application to this case: required to avoid adding the 2018/2025/EFSA interim counts as independent reports/trials. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare the relationship between reanalysis of the same reports and new independent events."
    },
    {
      "item_id": "N15",
      "question_type": "Collection period and reference date",
      "question": "Were the Lareb collection period and the historical reference dates of the material separated?",
      "needed": "Original analysis collection window and publication/review metadata",
      "role": "Required",
      "role_reason": "Required to avoid changing the end date of report collection into the publication/review date or the date of this lookup.",
      "application_exception": "The report collection end on 2023-12-31, the 2025 analysis, the original review on 2026-09-15, and the date of this review are different events.",
      "criterion": "Preserve the 2025 analysis's report collection window, 2007-08–2023-12-31, separately from publication/review dates.",
      "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed / C09: M04 §4.5, §4.6.3; limitations on the current material conversion reflect the user-defined scope and internal design / H02: Design-specific harm questions in M19 §19.2; temporal-relationship details are internally designed. Rationale for application to this case: required to avoid changing the end date of report collection into the publication/review date or the date of this lookup. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare the actual event associated with each date and the applicability of the material."
    },
    {
      "item_id": "N16",
      "question_type": "Report confirmation and duration",
      "question": "Are clinical confirmation, actual exposure duration, and completeness of collection of Lareb reports verified?",
      "needed": "Original report table of diagnosis/exposure/duration, detection/selection, and follow-up",
      "role": "Required",
      "role_reason": "Required to avoid treating reported neuropathy as consistently confirmed new-onset events.",
      "application_exception": "Blood B6 values or titles are not used to substitute for gaps in report selection, diagnosis, or exposure.",
      "criterion": "Check the clinical definition/confirmation, exposure/onset periods, alternative causes, and missed detection for each report.",
      "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is internally designed / H01: M19 §19.1.2–19.2.4; detailed distinctions are internally designed / H02: M19 §19.2 design-specific harm questions; details of temporal relationships are internally designed / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application. Rationale for application to this case: needed to avoid treating reported neuropathy as consistently confirmed new clinical events. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review reporting definitions, selection/detection processes, and individual temporal relationships."
    },
    {
      "item_id": "N17",
      "question_type": "Exposed-person denominator for reports",
      "question": "Is a denominator verified for calculating incidence among exposed persons from spontaneous reports?",
      "needed": "Data on all exposed persons, observation time by dose, all/confirmed events, and unreported cases",
      "role": "Required",
      "role_reason": "Needed to avoid converting report counts into probabilities of occurrence among all users or dose groups.",
      "application_exception": "Report counts, counts of blood tests, and content per tablet are not exposed-person counts or person-time.",
      "criterion": "Do not present incidence unless all exposed persons, observation time, and event counts for the same event/dose/duration have been verified.",
      "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptation is internally designed / H04: M19 §19.1.2–19.2.4; internal application / H09: Chamgap’s own interpretive boundaries. M19 principles are referenced; no formal causality tool was applied. Rationale for application to this case: needed to avoid converting report counts into probabilities of occurrence among all users or dose groups. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review the correspondence between report-based counts and the actual population at risk/observation time."
    },
    {
      "item_id": "N18",
      "question_type": "TGA selected-report signal",
      "question": "Can selection and overlap in TGA’s 32 reports and low-dose/multiple-product categories be verified?",
      "needed": "Original TGA tables of report selection, clinical confirmation, and overlap between dose/multiple-product categories",
      "role": "Required",
      "role_reason": "Needed to avoid mistaking the composition of selected reports for comparative risk among all users by dose.",
      "application_exception": "The 21 reports and 9 reports may overlap; the 32 reports are not substituted for all reports/exposed persons or fully confirmed events.",
      "criterion": "Verify the selection criteria, categories/overlap, and actual denominator meanings of 32·21·9, while retaining unverified selection processes as unverified.",
      "basis": "C04: M03 §3.2.1; detailed population conditions are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptation is internally designed / H04: M19 §19.1.2–19.2.4; internal application / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application. Rationale for application to this case: needed to avoid mistaking the composition of selected reports for comparative risk among all users by dose. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare selection criteria, category overlap, and detection/reporting bias."
    },
    {
      "item_id": "N19",
      "question_type": "Low-dose causality",
      "question": "Are comparative risk, causality, and a no-risk boundary at low doses established?",
      "needed": "Exposure/comparator, event, duration, confounding, and risk-estimate data for each low dose",
      "role": "Required",
      "role_reason": "Needed to avoid converting a possible signal from low-dose reports into confirmed causality at all low doses or safety at all low doses.",
      "application_exception": "The composition of reports involving ≤50 mg/day and the labeling warning for >10 mg are not the same biological threshold.",
      "criterion": "Retain the scope of dose-specific risk verification based on actual comparators/denominators, precise exposure, other causes/duration, and clinical events.",
      "basis": "H03: M19 §19.2.2–19.2.4, M03 §3.2.3; internal application / H04: M19 §19.1.2–19.2.4; internal application / H09: Chamgap’s own interpretive boundaries. M19 principles are referenced; no formal causality tool was applied. Rationale for application to this case: needed to avoid converting a possible signal from low-dose reports into confirmed causality at all low doses or safety at all low doses. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Distinguish the evidentiary level of spontaneous-report signals from that of comparative-risk/causal conclusions."
    },
    {
      "item_id": "N20",
      "question_type": "TB comparative estimate",
      "question": "Are the dose-specific comparative estimate and its uncertainty in the tuberculosis cohort verified?",
      "needed": "Tables of exposure/events, denominators, adjustment models, HR/CI, and follow-up by dose group",
      "role": "Required",
      "role_reason": "Needed to avoid transferring the reported HR to a causal RR for general supplement use or an exact incidence rate.",
      "application_exception": "The 144 people and 50 people (35% in the original) and HR 2.79 do not substitute for group-specific denominators/event counts or CI.",
      "criterion": "Distinguish the 200 versus 150 mg/day comparison and adjusted HR/P from the actual scope of verification of group-specific denominators/events, CI, and follow-up.",
      "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptation are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptation is internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application / E05: M15 §15.3.1–15.3.3; internal application / H03: M19 §19.2.2–19.2.4, M03 §3.2.3; internal application / H04: M19 §19.1.2–19.2.4; internal application. Rationale for application to this case: needed to avoid transferring the reported HR to a causal RR for general supplement use or an exact incidence rate. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare estimates and uncertainty for the same event/comparator/duration and analysis model."
    },
    {
      "item_id": "N21",
      "question_type": "TB nonrandomized design",
      "question": "Were the nonrandomized doses in the tuberculosis cohort and limitations on application to general supplement use preserved?",
      "needed": "Original recruitment/prescribing, population/concurrent treatment, and actual comparator design",
      "role": "Required",
      "role_reason": "Needed to avoid converting a nonrandomized comparison in a treatment setting into an RCT causal effect among healthy users.",
      "application_exception": "Do not equate the TB/HIV and terizidone/cycloserine context with general exposure to a single-ingredient supplement.",
      "criterion": "Indicate the original design, population/co-medication, and nonrandomized doses, and prevent transfer of the HR to an RR for general users.",
      "basis": "C04: M03 §3.2.1; detailed population conditions are internally designed / E01: M08 §8.1–8.2.3; internal application / H03: M19 §19.2.2–19.2.4, M03 §3.2.3; internal application / H05: M19 §19.2.2–19.2.4 design considerations; detailed confounding records are internally designed. Rationale for application to this case: needed to avoid converting a nonrandomized comparison in a treatment setting into an RCT causal effect among healthy users. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review the interpretive scope arising from the population, prescribing context, and nonrandomized comparison."
    },
    {
      "item_id": "N22",
      "question_type": "TB alternative explanations",
      "question": "Was confounding by tuberculosis/HIV, medications, and prescribing reasons sufficiently controlled?",
      "needed": "Original adjustment-model, prescribing/underlying-disease, medication, and exposure-follow-up data",
      "role": "Required",
      "role_reason": "Needed to avoid establishing the association with B6 dose as a cause independent of medications and diseases.",
      "application_exception": "The term adjusted HR alone does not eliminate residual confounding from prescribing indications, baseline neuropathy, or disease/co-medication.",
      "criterion": "Check model variables, prescribing reasons, baseline status/concurrent medications, exposure deviations, and residual confounding.",
      "basis": "H05: M19 §19.2.2–19.2.4 design considerations; detailed confounding records are internally designed / C04: M03 §3.2.1; detailed population conditions are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Rationale for application to this case: needed to avoid establishing the association with B6 dose as a cause independent of medications and diseases. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review actual measurement of adjustment variables and confounding associated with timing and prescribing."
    },
    {
      "item_id": "N23",
      "question_type": "TB endpoint and time denominator",
      "question": "Can the endpoint/time denominator for TB neuropathy be separated from other neuropsychiatric AE?",
      "needed": "Neuropathy-specific tables of definitions/confirmation, events/time, and missing data/discontinuation",
      "role": "Required",
      "role_reason": "Needed to avoid transferring the person-month incidence of all neuropsychiatric AE to sensory neuropathy.",
      "application_exception": "The mixed new/worsened count of 50 people is not a separate count of clinically confirmed new events or an exposure-time denominator.",
      "criterion": "Separately verify the definition, new/worsened status, follow-up/denominator, and missing data for neuropathy, and prevent transfer of the composite AE incidence.",
      "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is internally designed / H01: M19 §19.1.2–19.2.4; detailed distinctions are internally designed / H04: M19 §19.1.2–19.2.4; internal application / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application. Rationale for application to this case: needed to avoid transferring the person-month incidence of all neuropsychiatric AE to sensory neuropathy. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare attribution of the mixed endpoint, other AE, and observation time/participant flow."
    },
    {
      "item_id": "N24",
      "question_type": "CIAP population applicability",
      "question": "Was pre-existing disease in the CIAP case-control study distinguished from the question of new toxicity?",
      "needed": "Original population/design, baseline symptoms, and exposure timing/endpoints",
      "role": "Required",
      "role_reason": "Needed to avoid converting the association between prevalent CIAP and supplement use into risk of new onset.",
      "application_exception": "The 381 cases and 140 controls are not a population-at-risk denominator for a cohort with new exposure.",
      "criterion": "Indicate the context of the pre-existing CIAP case-control study and its role, which does not establish incident toxicity or guarantee absence of risk.",
      "basis": "C04: M03 §3.2.1; detailed population conditions are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is internally designed / H03: M19 §19.2.2–19.2.4, M03 §3.2.3; internal application / H09: Chamgap’s own interpretive boundaries. M19 principles are referenced; no formal causality tool was applied. Rationale for application to this case: needed to avoid converting the association between prevalent CIAP and supplement use into risk of new onset. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare the directness of the prevalent-case case-control study for the new-onset question and assess reverse causation."
    },
    {
      "item_id": "N25",
      "question_type": "Attribution of contrasting results",
      "question": "Were the nonsignificant blood-value result and the supplement-use association in CIAP both preserved?",
      "needed": "Original results tables, blood-value/supplement-use estimates, and authors’ interpretation",
      "role": "Required",
      "role_reason": "Needed to avoid omitting favorable/nonsignificant or contrary results and attributing all neuropathy to B6.",
      "application_exception": "Do not convert the blood-value P = 0.58 into a risk of 0, or the supplement-use OR into a causal RR for new toxicity.",
      "criterion": "Link the 381/140 participants’ 99/109 nmol/L values and P, the 31%/22% and OR/CI/P, and the authors’ limiting interpretation together according to their original locations.",
      "basis": "C08: M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is internally designed / H09: Chamgap’s own interpretive boundaries. M19 principles are referenced; no formal causality tool was applied. Rationale for application to this case: needed to avoid omitting favorable/nonsignificant or contrary results and attributing all neuropathy to B6. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare the results, directions, and uncertainties for different measurements/exposures separately."
    },
    {
      "item_id": "N26",
      "question_type": "Reverse causation and underlying causes",
      "question": "Are reverse causation and alternative causes in CIAP and reports sufficiently verified?",
      "needed": "Baseline symptoms, start/sequence of use, examinations/other tests, and alternative diseases/medications",
      "role": "Required",
      "role_reason": "Needed to review the possibility that B6 was used because of pre-existing symptoms, and neuropathy due to other causes.",
      "application_exception": "Elevated PLP or supplement use alone does not establish B6 causation or the cause of pre-existing disease.",
      "criterion": "Check the temporal order of symptoms/exposure, underlying disease/concurrent medication, selection/measurement, and alternative causes.",
      "basis": "H05: M19 §19.2.2–19.2.4 design considerations; detailed confounding records are internally designed / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application / C04: M03 §3.2.1; detailed population conditions are internally designed. Rationale for application to this case: needed to review the possibility that B6 was used because of pre-existing symptoms, and neuropathy due to other causes. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review reverse causation/confounding associated with exposure timing and disease selection/detection."
    },
    {
      "item_id": "N27",
      "question_type": "Older-adult combination-product cases",
      "question": "Can the combination product and actual long-term exposure in 3 older adults be verified?",
      "needed": "Original case-specific product/composition, dose/duration, baseline-status, and adherence data",
      "role": "Required",
      "role_reason": "Needed to avoid combining cases involving B1/B6/B12 combination tablets into population incidence for single-ingredient B6 products.",
      "application_exception": "Ages 80·83·83 years in 3 people and 600 mg/day for 3–10 years do not constitute an exposed-person denominator for a single-ingredient product or an individual recommended dose.",
      "criterion": "Distinguish combination composition, nominal pyridoxine dose, and duration/population from gaps in actual product, adherence, and concurrent exposure data.",
      "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptation are internally designed / H05: M19 §19.2.2–19.2.4 design considerations; detailed confounding records are internally designed / H08: M19 §19.1.2–19.2.4; internal application. Rationale for application to this case: needed to avoid combining cases involving B1/B6/B12 combination tablets into population incidence for single-ingredient B6 products. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare actual exposure in each case and the combination-product/older-adult context."
    },
    {
      "item_id": "N28",
      "question_type": "Long-term residual disability",
      "question": "Are individual recovery/disability assessments and long-term follow-up in the older-adult cases sufficiently verified?",
      "needed": "Original withdrawal/follow-up, neurological/gait assessments, alternative causes, and long-term denominators",
      "role": "Required",
      "role_reason": "Needed to avoid converting cases with no significant improvement 2 years after withdrawal into a probability of permanent damage or inability to recover in everyone.",
      "application_exception": "No significant improvement is not equivalent to confirmed complete permanent damage, a quantitative incidence rate, or recovery outcomes under other exposures.",
      "criterion": "Compare the scope of verification of original neurological/gait assessments, alternative causes, individual follow-up, and completeness of recovery. A summary stating that there was no significant improvement even 2 years after withdrawal is not treated as verification of a complete long-term assessment or a probability of permanent damage.",
      "basis": "H02: M19 §19.2 design-specific harm questions; details of temporal relationships are internally designed / H04: M19 §19.1.2–19.2.4; internal application / H08: M19 §19.1.2–19.2.4; internal application / H09: Chamgap’s own interpretive boundaries. M19 principles are referenced; no formal causality tool was applied. Rationale for application to this case: needed to avoid converting cases with no significant improvement 2 years after withdrawal into a probability of permanent damage or inability to recover in everyone. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review recovery speed/completeness and limitations of follow-up and alternative-cause assessment."
    },
    {
      "item_id": "N29",
      "question_type": "Unacquired candidates",
      "question": "Are the original results of candidates concerning recovery, absence of neuropathy, and high doses verified?",
      "needed": "S26/S27/S28 original abstracts/full texts and case/results tables",
      "role": "Required",
      "role_reason": "Needed to avoid using titles of inaccessible sources as confirmed positive/negative findings or quantitative contrary evidence.",
      "application_exception": "Do not convert S26/S27/S28 historical metadata/access failures into failures during this task, an effect of 0, or complete case tables.",
      "criterion": "Use only the actually verified scope of original results/populations, doses, durations, and confirmation; leave title/metadata candidates unverified.",
      "basis": "C03: M04 §4.5–4.6 data-collection/selection principles; separation of access from reading and the hyperlink contract are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is internally designed / C09: M04 §4.5, §4.6.3; limitations of the current material conversion follow the user’s scope and internal design / H07: M04 §4.6.1–4.6.2; adaptation for harm materials is internally designed. Rationale for application to this case: needed to avoid using titles of inaccessible sources as confirmed positive/negative findings or quantitative contrary evidence. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare candidate identity/access scope with the feasibility of extracting actual original results."
    },
    {
      "item_id": "N30",
      "question_type": "Adjacent treatment evidence",
      "question": "Can original observations for this harm endpoint be traced in copies of the same Levin paper?",
      "needed": "Tables of actual harm events, baseline status/exposure, and denominators/durations in that paper",
      "role": "Required",
      "role_reason": "Needed to avoid borrowing values from treatment evidence for pre-existing diabetic neuropathy and figures from the adjacent manuscript for this new harm table.",
      "application_exception": "S01/S02 are bibliographic/author copies with the same DOI/PMID, but the 6 evidence entries in source contain no detailed rows for those harm events.",
      "criterion": "Indicate the same-paper/copy relationship and do not fill in harm events, denominators, or doses/durations that are not currently retained.",
      "basis": "C01: M03 §3.1, §3.2.1–3.2.4 question-clarification principles; detailed separation rules are internally designed / C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / C03: M04 §4.5–4.6 data-collection/selection principles; separation of access from reading and the hyperlink contract are internally designed / H09: Chamgap’s own interpretive boundaries. M19 principles are referenced; no formal causality tool was applied. Rationale for application to this case: needed to avoid borrowing values from treatment evidence for pre-existing diabetic neuropathy and figures from the adjacent manuscript for this new harm table. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare the copy/abstract relationship and the scope for direct extraction of these new/worsened clinical events."
    },
    {
      "item_id": "N31",
      "question_type": "Roles of official documents",
      "question": "Were official assessments and re-citations excluded from counts of new independent human trials?",
      "needed": "Citation lineage in the original official documents, underlying reports, and native family/linked-source lists",
      "role": "Required",
      "role_reason": "Needed to avoid inflating counts of TGA/NIH/EFSA documents and re-citations of existing reports/experiments into independent replications.",
      "application_exception": "The authority of an official document does not substitute for individual events, access to original sources, or risk rates.",
      "criterion": "Link each official document’s background/regulatory/re-citation role to the native evidence families, without issuing an independent count of human studies or participants.",
      "basis": "C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / H07: M04 §4.6.1–4.6.2; adaptation for harm materials is internally designed / H09: Chamgap’s own interpretive boundaries. M19 principles are referenced; no formal causality tool was applied. Rationale for application to this case: needed to avoid inflating counts of TGA/NIH/EFSA documents and re-citations of existing reports/experiments into independent replications. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Trace re-citations/reanalyses of original experiments/reports and the roles of official documents."
    },
    {
      "item_id": "N32",
      "question_type": "Overall comparative risk",
      "question": "Are comparative risk, CI, and background risk applicable to all users verified?",
      "needed": "Actual exposed/unexposed, event/denominator, follow-up, RR/RD/CI, and background-risk data",
      "role": "Required",
      "role_reason": "Needed to avoid combining high-dose causality, cases/reports, and an HR from a special population into a single overall risk rate.",
      "application_exception": "Do not newly calculate a common RR/RD/NNH from case counts, OR, HR, and nutritional/sales criteria.",
      "criterion": "Retain the scope of verification of comparative estimates for the same vitamer/formulation, population, event, comparator, duration, and denominator/CI.",
      "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptation is internally designed / E05: M15 §15.3.1–15.3.3; internal application / H03: M19 §19.2.2–19.2.4, M03 §3.2.3; internal application / H04: M19 §19.1.2–19.2.4; internal application / H09: Chamgap’s own interpretive boundaries. M19 principles are referenced; no formal causality tool was applied. Rationale for application to this case: needed to avoid combining high-dose causality, cases/reports, and an HR from a special population into a single overall risk rate. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review the applicability of estimates, uncertainty, and absolute risk by population/formulation/duration."
    },
    {
      "item_id": "N33",
      "question_type": "Vulnerable groups and long-term applicability",
      "question": "Are form-specific long-term risks in vulnerable groups and pre-existing neuropathy verified?",
      "needed": "Population-specific formulation, baseline status, exposure, long-term event/follow-up, and treatment-context data",
      "role": "Required",
      "role_reason": "Needed to avoid extending adult high-dose/report signals to individual safety/risk rates in children, pregnancy, or kidney disease.",
      "application_exception": "Kidney disease with low B6 markers or deficiency/metabolic disease requiring treatment does not constitute evidence of high-dose safety.",
      "criterion": "Check actual exposure/long-term event data and applicability limitations for kidney/liver function, pregnancy/lactation, children, and pre-existing neuropathy.",
      "basis": "C04: M03 §3.2.1; detailed population criteria are internally designed / E08: M03 §3.2.1–3.2.4; details on dose, duration, and effect modification are internally designed / H08: M19 §19.1.2–19.2.4; internal application. Reason for application to this case: Needed to avoid extending adult high-dose evidence/reporting signals to individual safety/risk rates in children, pregnancy, or renal disease. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review special populations/treatment contexts and the applicability of existing evidence."
    },
    {
      "item_id": "N34",
      "question_type": "Minimum risk and cumulative exposure",
      "question": "Are the minimum risk dose/duration, individual no-risk boundary, and cumulative exposure established?",
      "needed": "Individual measured amounts/doses, duration/adherence, events, and comparison/denominator data",
      "role": "Required",
      "role_reason": "Needed to avoid turning unverified daily dose × duration into a new cumulative exposure or no-risk threshold.",
      "application_exception": "The dose–onset relationship at high doses and signals from low-dose reports represent different levels of evidence.",
      "criterion": "Do not present a threshold/cumulative exposure unless individual actual daily doses, duration/adherence, clinical events, and adequate risk comparisons have been verified.",
      "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for tests are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; adaptation of outcomes to each question is internally designed / H02: M19 §19.2 on design-specific harm questions; details of temporal relationships are internally designed / H04: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretation boundaries. M19 principles are referenced; no formal causality tool was applied. Reason for application to this case: Needed to avoid turning unverified daily dose × duration into a new cumulative exposure or no-risk threshold. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Review the actual links between dose, duration, cumulative exposure, and onset/background risk."
    },
    {
      "item_id": "N35",
      "question_type": "Nutritional upper intake levels",
      "question": "Have the jurisdictions/purposes of the FNB/EFSA upper intake levels been distinguished from clinical toxicity thresholds?",
      "needed": "Preserved FNB/EFSA editions, populations/risk assessments, and basis for UL derivation",
      "role": "Supporting",
      "role_reason": "Needed to avoid turning a nutritional upper intake level into an individual therapeutic dose recommendation/no-risk guarantee.",
      "application_exception": "The US 100 mg/day and EFSA 12 mg/day are not clinical comparative values obtained from the same harm study.",
      "criterion": "State the jurisdictions/methods, populations, and nutritional purposes of the preserved editions, and do not repurpose them as therapeutic doses, clinical thresholds, or no-risk guarantees.",
      "basis": "C09: M04 §4.5, §4.6.3; limitations on the current material conversion reflect the user's scope and internal design / H08: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretation boundaries. M19 principles are referenced; no formal causality tool was applied. Reason for application to this case: Needed to avoid turning a nutritional upper intake level into an individual therapeutic dose recommendation/no-risk guarantee. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare jurisdictions/purposes, editions/populations, and the roles of clinical risk evidence."
    },
    {
      "item_id": "N36",
      "question_type": "Label warning rules",
      "question": "Have TGA label warnings been distinguished from biological risk boundaries?",
      "needed": "Preserved TGA label warning sections, transition/application dates, and products covered",
      "role": "Supporting",
      "role_reason": "Needed to avoid mistaking a labeling criterion for the point at which risk begins/an individual safety boundary.",
      "application_exception": ">10 mg/day and the 2023-03-01 transition deadline are administrative events under the rules preserved as of 2026-09-15.",
      "criterion": "Specify the labeling purpose, jurisdiction, application reference date/transition date, and do not use them as clinical risk thresholds.",
      "basis": "C09: M04 §4.5, §4.6.3; limitations on the current material conversion reflect the user's scope and internal design / H09: Chamgap's own interpretation boundaries. M19 principles are referenced; no formal causality tool was applied. Reason for application to this case: Needed to avoid mistaking a labeling criterion for the point at which risk begins/an individual safety boundary. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Distinguish the roles and dates of administrative labeling and clinical risk evidence."
    },
    {
      "item_id": "N37",
      "question_type": "Future sales classification",
      "question": "Has the future TGA sales classification been distinguished from current prescription/labeling rules?",
      "needed": "Preserved TGA sections on sales classification/effective dates and products covered",
      "role": "Supporting",
      "role_reason": "Needed to avoid retroactively treating regulations scheduled for 2027 as current rules/clinically safe doses in 2026.",
      "application_exception": "Pharmacist control at >50–≤200 mg/day and prescription control at >200 mg/day are neither nutritional ULs nor equivalent risk categories.",
      "criterion": "At the reference date 2026-09-15, separately state the scheduled 2027-06-01 date, dose ranges, and sales purposes.",
      "basis": "C09: M04 §4.5, §4.6.3; limitations on the current material conversion reflect the user's scope and internal design / H09: Chamgap's own interpretation boundaries. M19 principles are referenced; no formal causality tool was applied. Reason for application to this case: Needed to avoid retroactively treating regulations scheduled for 2027 as current rules/clinically safe doses in 2026. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare current/future application dates and the purposes of sales, labeling, and nutritional criteria."
    },
    {
      "item_id": "N38",
      "question_type": "Funding and roles",
      "question": "Is the actual scope of verification of funding, product supply, and conflicts of interest known for each report?",
      "needed": "Original funding/COI, product supply, and design/analysis/reporting role declarations",
      "role": "Required",
      "role_reason": "Needed to avoid filling in indexed grants or unverified information as no funding/no industry involvement/independence.",
      "application_exception": "The 2018 no-funding statement, unverified 2025 funding, and NIH/Wellcome indexed support are not at the same level of verification.",
      "criterion": "Distinguish each report's actual declarations/indexing from unverified funding, supply/roles, and conflicts of interest.",
      "basis": "C10: Chamgap's own conditions for independence and attribution. The official methodology sections used in this pilot do not endorse all of these detailed items. Reason for application to this case: Needed to avoid filling in indexed grants or unverified information as no funding/no industry involvement/independence. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare each report's support/declarations with the scope of verification of actual research/product roles."
    },
    {
      "item_id": "N39",
      "question_type": "Advance plans and search scope",
      "question": "Is the actual scope of verification of registration, plans, and corrections/retractions sufficiently established?",
      "needed": "Registration, protocol/SAP, changes, and correction/retraction search logs/original publication records",
      "role": "Required",
      "role_reason": "Needed to avoid extending unverified information/the recorded search scope into absence of preregistration, absence of corrections, or integrity of the entire literature.",
      "application_exception": "An empty registry_id is not proof of no registration, and the search_record wording is not evidence that the search logs were actually read in this review.",
      "criterion": "Verify actual registration/protocols, data collection/SAP, changes, correction/retraction searches, and their scope, and leave unavailable original logs unverified.",
      "basis": "C09: M04 §4.5, §4.6.3; limitations on the current material conversion reflect the user's scope and internal design / E06: M08 Table 8.2.a, M04 §4.6.3; internal application / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application. Reason for application to this case: Needed to avoid extending unverified information/the recorded search scope into absence of preregistration, absence of corrections, or integrity of the entire literature. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare advance plans/changes and original reports with the scope of searches/access."
    },
    {
      "item_id": "N40",
      "question_type": "Distinguishing reading and dates",
      "question": "Have the current summary reading, historical access to originals, and review/access dates been distinguished?",
      "needed": "Original bytes of the currently preserved archived summaries, citation access locations/identities, and access-date records",
      "role": "Required",
      "role_reason": "Needed to avoid upgrading the reading of preserved archived summaries to reading original full-text papers in this review.",
      "application_exception": "Do not reuse citations' historical access_level/location or the global verified_date as current full-text access/individual access dates.",
      "criterion": "Record the actual local summary locations/SHA separately from external access not attempted/materials unread, historical material types/access, and empty per-report access dates.",
      "basis": "C03: M04 §4.5–4.6 principles for material collection/selection; separation of access and reading and the hyperlink contract are internally designed / C09: M04 §4.5, §4.6.3; limitations on the current material conversion reflect the user's scope and internal design. Reason for application to this case: Needed to avoid upgrading the reading of preserved archived summaries to reading original full-text papers in this review. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare material types, original locations, historical/current reading events, and dates."
    },
    {
      "item_id": "N41",
      "question_type": "Personal treatment boundary",
      "question": "Has the original safety warning been kept from becoming personal treatment/discontinuation instructions?",
      "needed": "Original safety warning and personal application/treatment boundary",
      "role": "Required",
      "role_reason": "Needed to avoid turning harm information into instructions to stop/replace prescriptions or take individual doses.",
      "application_exception": "The blue record statuses in the review table and the original warning are not individual safety guarantees or self-treatment instructions.",
      "criterion": "Preserve the original safety information and assessment limitations, and do not newly assign individual recommended doses or instructions for self-directed dose escalation/prescription discontinuation.",
      "basis": "C01: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed / H09: Chamgap's own interpretation boundaries. M19 principles are referenced; no formal causality tool was applied. Reason for application to this case: Needed to avoid turning harm information into instructions to stop/replace prescriptions or take individual doses. No formal causality/harm grading assessment was performed.",
      "condition_origin": "The development conditions, designed after this case had already been read, were actually frozen in advance. This was not automated machine copying, blinding/clinical preregistration, or methodological certification.",
      "proposed_research": "Compare the boundary between public informational statements and personal treatment instructions with the actual original values."
    }
  ],
  "language": "en",
  "translation_date": "2026-11-02"
}