{ "title": "Oral single-active-ingredient pantothenic acid (vitamin B5) supplementation × Reduction in inflammatory lesion counts in adults with mild-to-moderate facial acne", "criteria_version": "NGM-v3099-ORAL-SINGLE-B5-ACNE-INFLAMMATORY-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 document the question, eligibility criteria, and reasons for changes, and distinguish intervention variants.", "review_level": "Reuse of previously preserved HTML and principles from 1585. This is not new reading of full methodology, application of an official tool, or certification in this review." }, { "id": "M04", "version": "Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-04", "section": "§4.5, §4.6.1–4.6.3, MECIR C42", "official_principle": "Distinguish and link studies and reports, and do not exclude a study solely because outcomes are unreported.", "review_level": "Reuse of previously preserved HTML and principles from 1585. This is not new reading of full methodology, application of an official tool, or certification in this review." }, { "id": "M08", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-08", "section": "§8.1–8.2.3, Table 8.2.a", "official_principle": "Fix the outcome and effect of interest, and review randomization, deviations, missing data, measurement, and selective reporting.", "review_level": "Reuse of previously preserved HTML and principles from 1585. This is not new reading of full methodology, application of an official tool, or certification in this review." }, { "id": "M15", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-15", "section": "§15.2.4, §15.3.1–15.3.3", "official_principle": "Distinguish effect estimates, intervals, importance, and applicability. Sample size alone does not determine precision.", "review_level": "Reuse of previously preserved HTML and principles from 1585. This is not new reading of full methodology, application of an official tool, or certification in this review." }, { "id": "M19", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-19", "section": "§19.1.2, §19.2.1–19.2.4", "official_principle": "Harm questions may require designs, populations, and follow-up different from those for efficacy. Case reports do not establish incidence.", "review_level": "Reuse of previously preserved HTML and principles from 1585. This is not new reading of full methodology, application of an official tool, or certification in this review." } ], "status_dictionary": { "Met": "The original identity, values, and interpretive boundaries were verified in archived materials. This is separate from clinical sufficiency or certification.", "Partly verified": "Some material has been linked, but directness, detailed data, and comparison remain unresolved.", "Unverified": "The direct material/values needed within the preserved scope actually read are unverified. This does not mean no effect, 0 events, or incomplete review of the production work.", "Not applicable": "The obligation for expansion outside the narrow assessed question is not applicable. This is not a substitute for unread material.", "Not applicable (alias)": "Display alias for Not applicable.", "Not read": "External original materials were not directly read in this review; this is separate from the current reading of summaries.", "Conflicting information": "Original disagreement within the same item; no arbitrary correction.", "Review incomplete": "Individual review of table production remains incomplete. This is distinguished from insufficient evidence." }, "schema_version": "chamgap-public-criteria-1.0", "condition_origin": "Chamgap’s own application conditions", "requirements": [ { "item_id": "N01", "question_type": "Separate claim", "question": "Which single question is linked to the original verdict URL?", "needed": "The current assessment target, facets, empty subclaims, canonical URL, and identity of the related 028.", "role": "Required", "role_reason": "Required to avoid merging other skin effects or the existing mixed claim 028 into the efficacy of the single ingredient assessed here.", "application_exception": "Korean/English versions and adjacent outcomes such as total lesions do not automatically generate separate independent claims.", "criterion": "Link the original /ko/effect to adult facial acne, oral pantothenic acid as the sole active ingredient, inflammatory lesion counts, and a placebo comparison with the same background treatment.", "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed — internal adaptation for a separate claim. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Before incorporating new material, use an inclusion/exclusion table to compare the assessment target with the population, intervention, and endpoint of each result." }, { "item_id": "N02", "question_type": "Sole active ingredient", "question": "Was the effect of pantothenic acid alone distinguished from the product effect?", "needed": "Material documenting all active ingredients, the exact salt, actual route, product, and batch of the single-active-ingredient formulation.", "role": "Required", "role_reason": "The presence of an ingredient alone cannot establish its isolated effect.", "application_exception": "Calcium pantothenate and the free acid are not automatically treated as equivalent; dexpanthenol and topical/intramuscular material are kept within the boundaries of adjacent evidence.", "criterion": "Verify whether the exact active ingredient, molecule, and route match the fixed question, and separate results from combination products.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for tests are internally designed; question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed — internal adaptation for a sole active ingredient. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Code each trial's intervention in a table of ingredients, salts, routes, and concurrent ingredients, and first assess direct comparability." }, { "item_id": "N03", "question_type": "Level of reading", "question": "Was summary reading in this review distinguished from historical access to original texts?", "needed": "The preserved URL, location, and access_level for each citation, and any records of individual access dates/acquired copies, if available.", "role": "Required", "role_reason": "Required to avoid mistaking an external link or historical full_text for full-text reading in this review.", "application_exception": "Because the original citation has no access date, leave the value empty and record the global verified_date separately as the material review date.", "criterion": "Separate the currently archived summaries actually read, each report's historical access_level, external access not attempted/material not read in this review, and the absence of access dates.", "basis": "Material collection/selection principles in M04 §4.5–4.6; separation of access and reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limitations on the current material conversion reflect the user's scope and internal design — internal adaptation for the level of reading. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "For each actual acquisition event, record document type, bytes, verification location, and access/reading times separately, and compare them with the summary reader." }, { "item_id": "N04", "question_type": "Report and trial families", "question": "Were the Yang main text and supplementary slide kept from being double-counted as trials?", "needed": "Each report's DOI, year, trial identity, supplementary-material linkage, and original evidence family_id.", "role": "Required", "role_reason": "Required to avoid adding a paper and its appendix as independent replications or assuming that materials from different years of the same brand concern an identical batch.", "application_exception": "S03 is the original F02 uncontrolled material from 2012. Even with the same Pantothen brand, batch identity with S01 is unverified.", "criterion": "Link S01/S02 to the same 2014 Yang family, and distinguish the original F01–F04 labels from a count of independent trials.", "basis": "Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application — internal adaptation for report and trial families. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Group related reports in a trial-identity table and compare titles, DOI, duration, populations, and batches to identify duplication and unestablished matters." }, { "item_id": "N05", "question_type": "Population and selection", "question": "Does the material directly match adults with mild-to-moderate facial acne?", "needed": "Tables of diagnosis, age/severity distributions, inclusion/exclusion, and baseline treatment in single-active-ingredient trials.", "role": "Required", "role_reason": "The label facial acne alone does not establish that populations and clinical selection are the same.", "application_exception": "The phrase mild-to-moderate facial acne in the title of an adjacent study is not extended into verification of all actual population details.", "criterion": "Compare diagnosis, age, severity, lesion location, inclusion/exclusion, and the actual directly eligible population.", "basis": "M03 §3.2.1; detailed population criteria are internally designed — internal adaptation for population and selection. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Prepare an eligibility table by diagnosis, severity, and baseline treatment to review differences between the original target population and study populations." }, { "item_id": "N06", "question_type": "Deficiency boundary", "question": "Was the hypothesis of deficiency correction distinguished from efficacy for acne in general?", "needed": "Baseline nutritional status, methods of identifying deficiency, and direct comparative results within that stratum.", "role": "Supplementary; required for extension to deficiency", "role_reason": "Required to avoid transferring a deficiency hypothesis to efficacy in an unverified general acne population.", "application_exception": "Unverified baseline status is not filled in as normal or deficient. The S05 hypothesis is not a single-active-ingredient RCT with results.", "criterion": "Distinguish baseline pantothenic acid status, deficiency diagnosis, and correction outcomes from a comparison of monotherapy for acne.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed — internal adaptation for the deficiency boundary. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Separate deficient and nondeficient strata only in studies with baseline-status data, and compare whether effect modification was prespecified." }, { "item_id": "N07", "question_type": "Salt, batch, and quality", "question": "Were the salt, formulation, and manufacturing batch of the eligible single-active-ingredient product verified?", "needed": "Trial-batch manufacturing/composition certificates, complete label, salt and labeled-amount basis, and formulation-quality data.", "role": "Required", "role_reason": "Product names and labeled amounts alone cannot establish the actual sole active ingredient or exposure.", "application_exception": "The efficacy and doses of the calcium salt and free acid are not converted as equivalent. The presence of excipients alone does not establish that a product has multiple active ingredients.", "criterion": "Link the exact salt, manufacturing source, purity, batch, release formulation, and tablet/capsule to the actual trial product.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for tests are internally designed — internal adaptation for salt, batch, and quality. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Separate the salt, active-amount basis, excipients, and purity in batch records, and compare the trial intervention with the label for agreement." }, { "item_id": "N08", "question_type": "2014 product composition", "question": "Can the sole-active-ingredient status of the 2014 Pantothen product be verified?", "needed": "The complete active composition, exact salt, and batch certificate for the 2014 batch, and comparator ingredients.", "role": "Required", "role_reason": "Required to avoid accepting the product effect in a related RCT as the effect of the selected ingredient alone.", "application_exception": "The fact that the 2012 product had multiple ingredients does not establish that the 2014 batch was identical.", "criterion": "Verify all active ingredients in the relevant 2014 trial batch and assess whether its effect can be separately attributed to B5.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for tests are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — internal adaptation for 2014 product composition. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Compare the 2014 batch composition with a placebo under the same background treatment, and review whether a comparison isolates the single ingredient." }, { "item_id": "N09", "question_type": "2012 combination product", "question": "Were the other ingredients and dosing of the 2012 product distinguished?", "needed": "The complete active composition, amounts/units of each ingredient, dosing records, and product-batch data for 2012.", "role": "Required (attribution of related material)", "role_reason": "Required to avoid repurposing within-group results for a combination product as comparative efficacy of pantothenic acid alone.", "application_exception": "Complete composition or unit extractions absent from the current archived summaries are not supplemented from old ledgers or the brand name.", "criterion": "Attribute the multiple ingredients, L-carnitine, and dosing frequency in 2012 and the 8-week observation to that product alone.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for tests are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — internal adaptation for the 2012 combination product. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Reconstruct a table of actual amounts and dosing frequency by ingredient, leave unverified composition empty, and assess the possibility of an isolated comparison." }, { "item_id": "N10", "question_type": "Labeled and actual amounts", "question": "Was the reported dose kept from being converted into a therapeutic dose for the single-active-ingredient product?", "needed": "Labeled-amount basis, frequency, actual use/adherence, diet, and other supplemental intake for the eligible single-active-ingredient product.", "role": "Required", "role_reason": "Required to avoid presenting the adjacent product's 2.2 g/day as a verified dose for acne treatment with the single ingredient alone.", "application_exception": "Salt conversions, actual intake, and optimal doses absent from the original material are not calculated.", "criterion": "Distinguish the product's reported amount from the actual active amount, adherence, and total intake for the single-active-ingredient product.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for tests are internally designed; M03 §3.2.1–3.2.4; details on dose, duration, and effect modification are internally designed — internal adaptation for labeled and actual amounts. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "After reviewing adherence while separating labeled amounts from actual exposure, assess whether there are direct dose comparisons of the same formulation." }, { "item_id": "N11", "question_type": "Duration and time points", "question": "Were product observation periods distinguished from eligible single-active-ingredient time points?", "needed": "Start/end dates, assessment schedules, duration of observation, and endpoint-specific timelines for the single-active-ingredient product.", "role": "Required", "role_reason": "Required to avoid combining adjacent comparisons of different durations into a direct effect at a single time point.", "application_exception": "S04's 2 months are not newly converted to 8 weeks, and nominal duration is not assumed to establish actual exposure or complete follow-up.", "criterion": "Attribute 12 weeks, 8 weeks, and 2 months to their respective reports, and keep treatment/assessment time points for the eligible single-active-ingredient product separate.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for tests are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M03 §3.2.1–3.2.4; details on dose, duration, and effect modification are internally designed — internal adaptation for duration and time points. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Separate dosing, assessment, and analysis time points by report in a timeline, and review comparability of the same endpoint at the same time point." }, { "item_id": "N12", "question_type": "Placebo and background treatment", "question": "Was the difference between the single-active-ingredient product and placebo under the same background treatment verified?", "needed": "Complete composition of the single-active-ingredient product/placebo, common treatment by group, rescue treatment/changes, and adherence records.", "role": "Required", "role_reason": "Required to avoid attributing contributions from concurrent ingredients or other treatments to pantothenic acid alone.", "application_exception": "Compare the effect of interest and actual management in each group rather than requiring complete identity of all changes in both groups.", "criterion": "Separate placebo composition, concomitant/rescue treatment, adherence, and deviations from the difference in the sole active ingredient.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for tests are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — internal adaptation for placebo and background treatment. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Design a comparison of the single-active-ingredient product and a matching placebo under the same background treatment, and prespecify recording and analysis of changes in concomitant/rescue treatment." }, { "item_id": "N13", "question_type": "Allocation and concealment", "question": "Were the actual allocation process and baseline balance verified?", "needed": "Random sequence, concealment, group-specific baseline tables, and original methods text for the direct single-active-ingredient comparison.", "role": "Required (causal efficacy)", "role_reason": "The labels randomized and double-blind alone cannot establish that all allocation and confounding problems were resolved.", "application_exception": "Preserve the uncontrolled S03 material as well, and do not automatically assign Not applicable for crossover/cluster design when the direct design is unverified.", "criterion": "Compare the allocation method, concealment, and baseline balance for the selected result separately from the study label.", "basis": "M08 §8.1–8.2.3; internal application — internal adaptation for allocation and concealment. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Compare the methods and baseline tables against outcome-specific allocation/concealment questions, and separate unverified elements." }, { "item_id": "N14", "question_type": "Baseline means and SD", "question": "Were 15.3(8.9) and 17.3(14.3) kept from being used as effects?", "needed": "The baseline table's means/SDs, groups/time points, and denominators, and the endpoint/change results table for the outcome concerned.", "role": "Required (numerical attribution)", "role_reason": "Needed to avoid converting baseline lesion counts or parenthesized SDs into single-ingredient effects and precision values.", "application_exception": "Do not newly calculate endpoint differences, differences in change, or CI from baseline SDs and sample sizes.", "criterion": "Distinguish the baseline inflammatory-lesion means and SDs in Table 1 from endpoint values, differences in change, SE, and CI.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.1–8.2.3; internal application — internal adaptation for baseline means/SDs. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Cross-check each numerical value in the table by group, time point, and statistic, and extract baseline values separately from treatment results." }, { "item_id": "N15", "question_type": "Endpoint type", "question": "Were inflammatory lesions separated from total lesions and other assessments?", "needed": "Lesion classifications, counting definitions, the primary/secondary endpoint table, and between-group results for each endpoint.", "role": "Required", "role_reason": "Needed to avoid automatically substituting total-lesion results for the original inflammatory-lesion effect.", "application_exception": "Do not fill in values or priorities for other scales, such as IGA, that are absent from the currently archived summaries.", "criterion": "Separate the definitions/priorities of inflammatory-lesion counts, total lesions, noninflammatory lesions, and other clinical assessments.", "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 — internal adaptation for endpoint types. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Specify inflammatory lesions as the prespecified endpoint of interest and report total lesions, noninflammatory lesions, and other scales as separate results." }, { "item_id": "N16", "question_type": "Counting and blinding", "question": "Can the actual procedures for lesion counting and assessor blinding be determined?", "needed": "Lesion-counting manual, assessor training/agreement, maintenance of blinding, and collection schedules by group.", "role": "Required", "role_reason": "Needed to avoid judging a measurement to be objective or a surrogate endpoint merely because it is called an observer count.", "application_exception": "Do not repurpose the double-blind designation as verification of actual lesion-assessor blinding or measurement limitations.", "criterion": "Verify inflammatory-lesion assessors, counting rules, assessment time points, blinding, and measurement differences between groups.", "basis": "M08 Table 8.2.a, M03 §3.2.4; internal application — internal adaptation for counting/blinding. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Review blinded assessment and agreement in advance using standardized counting procedures, and record differences in measurement schedules between groups." }, { "item_id": "N17", "question_type": "Allocation and evaluation denominators", "question": "Which analyses do 48/41 and the group-specific 20/21 counts belong to?", "needed": "Flow diagram, group-specific allocation/completion/analysis table, endpoint-specific analysis n, and group identification.", "role": "Required", "role_reason": "Needed to avoid immediately converting an evaluable sample into the target endpoint's ITT denominator or group-specific participants.", "application_exception": "Do not newly map the group-specific 20/21 order in the current n field to product/placebo without the original material.", "criterion": "Distinguish allocation, evaluation, and group-specific reported counts from the inflammatory-lesion analysis denominator, and do not infer group correspondence.", "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 — internal adaptation for allocation/evaluation denominators. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Separate the flow table into allocation, completion, and target-endpoint analysis, and compare denominator links by group/time point." }, { "item_id": "N18", "question_type": "Missing data and analysis populations", "question": "Were people who were not evaluated and the handling of ITT/PP verified?", "needed": "Reasons for loss to follow-up/discontinuation by group, ITT/PP definitions, missing-data handling, and sensitivity analyses.", "role": "Required", "role_reason": "Needed to avoid transferring selected evaluable results to an effect among everyone allocated.", "application_exception": "Do not arbitrarily assign ITT or PP if the original text does not specify the analysis.", "criterion": "Link reasons for missing data/discontinuation, their distribution by group, analysis populations, and imputation/sensitivity handling to the target endpoint.", "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 — internal adaptation for missing data/analysis populations. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Distinguish interest in the effect of assignment from the effect of adherence, and compare analysis plans/sensitivity analyses that include missing endpoint data." }, { "item_id": "N19", "question_type": "Target between-group effect", "question": "Are the between-group difference, P, and CI for inflammatory lesions with the single-ingredient intervention available?", "needed": "Results table for the directly relevant single-ingredient intervention, including endpoint/change means, variances, group-specific n, analysis model, P, and CI.", "role": "Required", "role_reason": "Needed to avoid filling the gap in single-ingredient inflammatory-lesion effects with numbers for total lesions or combination products.", "application_exception": "Do not calculate new effects or intervals by reconstructing graphs or using baseline SDs or other lesion counts.", "criterion": "Link the directly eligible single-ingredient intervention's between-group difference in inflammatory-lesion change, endpoint difference, P, CI, and denominators to the exact analysis.", "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; M15 §15.3.1–15.3.3; internal application — internal adaptation for the target between-group effect. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "In a single-ingredient intervention–placebo comparison with the same background treatment, report between-group estimates and intervals for the prespecified inflammatory endpoint by analysis population." }, { "item_id": "N20", "question_type": "Variance and intervals", "question": "Was precision kept from being filled in using baseline SDs or significance for other endpoints?", "needed": "Variances of inflammatory-lesion change/endpoint values, group-specific n, and SE/CI appropriate to the analysis.", "role": "Required", "role_reason": "Because the presence of sample sizes or baseline SDs alone cannot establish the precision of the target effect.", "application_exception": "Do not convert the existing empty axes.precision value into a score of 0, high precision, or a new interval.", "criterion": "Distinguish the target effect's variance/SE/CI from baseline means (SDs) and P for other endpoints.", "basis": "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 — internal adaptation for variances/intervals. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Compare change-score variances and intervals appropriate to the original analysis, and record limitations imposed by missing-data assumptions on interval interpretation." }, { "item_id": "N21", "question_type": "Favorable total-lesion values", "question": "Were the outcomes and denominators to which P=0.0197 and 68.21% refer preserved?", "needed": "Original total-lesion results table, calculation formula/denominator for 68.21%, group/time point, and effect direction.", "role": "Required (preservation of related results)", "role_reason": "Needed to retain favorable adjacent results without repurposing them as single-ingredient inflammatory-lesion effects.", "application_exception": "Do not accept 68.21% as an additional reduction relative to placebo or an effect of pantothenic acid alone.", "criterion": "Attribute the total-lesion P and the 68.21% wording only to the original product/analysis, and indicate that the calculation formula and denominator are unverified.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; 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 — internal adaptation for favorable total-lesion values. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Compare the wording's formula, denominator, group, and endpoint with the original table, and verify from the original definition whether it represents an additional effect relative to placebo." }, { "item_id": "N22", "question_type": "Separating ingredient contributions", "question": "Can the contribution of B5 be separated from the combination product's effect?", "needed": "Full composition, ingredient-specific comparators or appropriate factorial comparisons, and common-background data.", "role": "Required", "role_reason": "Because a randomized product-level comparison does not automatically estimate a separately identified ingredient-level causal effect.", "application_exception": "Do not delete the product results as invalid; retain them as adjacent results for the original product.", "criterion": "Check whether there is a comparison in which other active ingredients and common treatments are held constant and only B5 differs.", "basis": "M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — internal adaptation for separating ingredient contributions. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Review a single-ingredient comparison in which only B5 differs, or a factorial design with ingredient contributions defined in advance." }, { "item_id": "N23", "question_type": "Uncontrolled within-group results", "question": "Was the 2012 change of 20.45→11.18 kept from being converted into a between-group effect?", "needed": "The 2012 results table, global-lesion definition, within-group analysis, flow of 11 enrolled/10 completed, and detailed composition.", "role": "Required (preservation of related results)", "role_reason": "Needed to distinguish improvement over time from additional improvement relative to a comparator.", "application_exception": "Do not newly calculate placebo effects, additional effects, or reduction percentages from within-group changes.", "criterion": "Attribute within-group changes in global lesions from an uncontrolled, open-label study to their separate product/endpoint/denominator.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M08 §8.2.2, M15 §15.3.1; internal application — internal adaptation for uncontrolled within-group results. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Extract within-group results separately, and compare alternative explanations involving temporal change, regression, and concurrent treatment against comparative data." }, { "item_id": "N24", "question_type": "Other routes and no detected difference", "question": "Was Saki's P=0.476 kept from being used as an effect of 0 for oral single-ingredient supplementation?", "needed": "Saki's actual molecule/formulation, intramuscular administration, adapalene background, analysis groups/time points, and original results table.", "role": "Required (boundaries for contrary results)", "role_reason": "Needed to retain the related nonsignificant result without mistaking it for repeated counterevidence against oral pantothenic acid.", "application_exception": "Preserve the dexpanthenol description in the original KO and the Pantothenic Acid wording in the paper title; do not resolve molecular identity from the names alone.", "criterion": "Attribute the P for the endpoint-value comparison involving a different route, molecule, and background only to that analysis.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed — internal adaptation for other routes/no detected difference. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Compare differences in the reported title, actual administered formulation, route, background, and endpoint timing to distinguish the basis for judging directness." }, { "item_id": "N25", "question_type": "Historical hypotheses and bibliographic records", "question": "Was the Leung bibliographic lead kept from being converted into an eligible RCT result?", "needed": "Leung's original text, actual study design/population, single-ingredient oral intervention, and between-group inflammatory-lesion results.", "role": "Required (candidate boundaries)", "role_reason": "Needed to avoid creating a single-ingredient RCT or a causal effect merely because a citation exists.", "application_exception": "Do not interpret unacquired full text or an unverified design as a negative result or absence of research.", "criterion": "Distinguish indexing, hypotheses, and citations in other papers from actual controlled designs and verified results.", "basis": "The distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application; M04 §4.5, §4.6.3; limitations on the current material conversion reflect the user's scope and internal design; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed — internal adaptation for historical hypotheses/bibliographic records. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "If the original text is acquired, separate hypotheses from observational/trial results and compare them with the current question using an eligibility table." }, { "item_id": "N26", "question_type": "Legacy and other endpoints", "question": "Were S09–S11 kept from being repurposed as direct acne results?", "needed": "The original citations' populations, routes, and endpoints, and the scope of legacy carryover; original results if needed.", "role": "Required (attribution of related material)", "role_reason": "Needed to avoid combining different populations, routes, and measures merely because they share a vitamin name or concern skin.", "application_exception": "The legacy 028 or reference files are not labeled as directly read in this review, and their clinical numerical values are not inherited.", "criterion": "Distinguish material carried over from legacy 028, female hair loss, and topical dexpanthenol/hydration/barrier outcomes from the current question.", "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed; the distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed — internal adaptation for legacy/other endpoints. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Separate each carried-over citation into a population, molecule, route, and endpoint table to distinguish discovery context from direct results." }, { "item_id": "N27", "question_type": "Registration and analysis plans", "question": "Can the planned inflammatory endpoints/time points be compared with the reports?", "needed": "Official registration history, protocol, SAP, reasons for endpoint changes, and reported results.", "role": "Required", "role_reason": "Because material is needed to compare reporting of total lesions as primary and inflammatory lesions as secondary with advance plans and possible selective reporting.", "application_exception": "Do not convert an empty nct value or gaps in registration access into nonregistration, confirmed selective reporting, or negative results. The S02 slide is not a protocol.", "criterion": "Compare the target endpoints/time points/denominators in registrations, protocols, and SAP with actual reports, and explicitly state nonacquisition.", "basis": "M08 Table 8.2.a, M04 §4.6.3; internal application; M04 §4.5, §4.6.3; limitations on the current material conversion reflect the user's scope and internal design — internal adaptation for registration/analysis plans. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Compare initial registration/change histories, protocols, and SAP with report endpoints, time points, and analyses step by step." }, { "item_id": "N28", "question_type": "Funding and conflicts of interest", "question": "Were sponsorship, institutions, declarations, and unverified information distinguished?", "needed": "Research funding/publication fees, product provision, author employment/patents, COI, and sponsor roles in the research.", "role": "Supplementary; required for claims of independence", "role_reason": "Needed to avoid automatically accepting a declaration of no conflicts of interest or unverified funding as independent replication or absence of bias.", "application_exception": "Do not exclude results merely because sponsorship exists, and do not sustain a claim of independence using unverified information.", "criterion": "Record each report's funding, publication fees, affiliations, and COI declarations separately from unverified employment/product provision/patents.", "basis": "Chamgap's own conditions for independence and attribution. The official methodology sections in this pilot do not endorse all of these detailed items — internal adaptation for funding/conflicts of interest. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Compare funding sources, institutions, employment, patents, and sponsor roles by report in a table, and preserve results regardless of their direction." }, { "item_id": "N29", "question_type": "Direct replication and differences", "question": "Were differences among related studies kept from being counted as independent replications of single-active-ingredient treatment?", "needed": "Unique trial identity, eligibility/results tables, single-active-ingredient composition, each endpoint/time point, and information on independent institutions.", "role": "Required (interpretation of replication)", "role_reason": "Needed to avoid turning results from the same brand, appendices, or other routes into reproduction or replicated refutation of efficacy for inflammatory lesions from a single active ingredient.", "application_exception": "Do not extend unverified direct eligibility to 0 studies worldwide or assign Not applicable to unverified study-family information.", "criterion": "Distinguish direct replications that match the report family, single-active-ingredient status, population, route, lesion type, and time point from adjacent results.", "basis": "Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — internal adaptation for direct replication and differences. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "First compare eligibility and outcome differences by trial, then review direct independent replication separately after deduplication." }, { "item_id": "N30", "question_type": "Clinical importance", "question": "Is there evidence for judging the clinical importance of a difference in lesion counts?", "needed": "Between-group effects/CI for the target inflammatory lesions, evidence of importance from the patient's perspective, and prespecified criteria.", "role": "Required (interpretation of importance)", "role_reason": "Needed to avoid declaring a clinically sufficient effect for the original question based only on significance for total lesions or study size.", "application_exception": "Do not assign numerical values to MCID, a minimum lesion difference, sample size, or duration without supporting evidence.", "criterion": "Link direct effects/intervals separately to criteria for a lesion difference that matters to patients.", "basis": "M15 §15.3.1–15.3.3; internal application — internal adaptation for clinical importance. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Review criteria linking patient experience to lesion differences, then present their relationship to the original intervals within a prespecified interpretation framework." }, { "item_id": "N31", "question_type": "Mechanistic and clinical boundaries", "question": "Were NAD/skin-hydration results kept from being used as effects on inflammatory lesions?", "needed": "Definition of the selected endpoint and the actual evidence and interpretive scope for each related mechanism/other clinical measure.", "role": "Supplementary; required for expansion to other clinical questions", "role_reason": "Needed to prevent mechanistic plausibility or skin relevance from substituting for the original question of oral single-active-ingredient efficacy.", "application_exception": "Because the lesions themselves are the treatment target, do not impose clinical-event/mortality trials as mandatory for this lesion-count question.", "criterion": "Distinguish the lesion count being treated from mechanisms, nutritional markers, topical barrier/hydration, and separate quality-of-life/event questions.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is internally designed; M03 §3.2.4; internally defined extension boundaries — internal adaptation for mechanistic and clinical boundaries. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Record mechanistic explanations and clinical lesion comparisons as separate lines of evidence, and handle new questions such as quality of life or scarring through a separate boundary review." }, { "item_id": "N32", "question_type": "Obligations for expanded questions", "question": "Are optimal dose, persistence after discontinuation, and subgroup effects imposed as mandatory?", "needed": "Direct dose comparisons, discontinuation/long-term follow-up, and prespecified subgroup and interaction data when making expanded claims.", "role": "Supplementary; required only for the relevant expansion", "role_reason": "Needed to avoid making every dose, long-term, and subgroup study outside the assessed question universally mandatory.", "application_exception": "Unverified actual doses and assessment time points for the single-active-ingredient product remain under the separate required conditions N10/N11 and are not erased by this Not applicable status.", "criterion": "Treat claims about optimization, persistence, and subgroups that are absent from the current narrow lesion-count question as separate questions.", "basis": "M03 §3.2.1–3.2.4; details on dose, persistence, and effect modification are internally designed — internal adaptation for obligations for expanded questions. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "If an expanded question is raised, separately design direct dose comparisons, follow-up after discontinuation, or a prespecified effect-modification plan." }, { "item_id": "N33", "question_type": "Adverse-event records", "question": "Was the lack of reported serious adverse events in a short combination-product study kept from being turned into safety?", "needed": "Tables of adverse events by arm, event/person counts, collection methods, denominators/durations, and discontinuation/missing data for a single-active-ingredient product.", "role": "Supplementary; required for safety interpretation", "role_reason": "Needed to avoid generalizing nonreporting in a small combination-product study into 0 events during long-term single-active-ingredient use or safety certification.", "application_exception": "Do not calculate unreported event counts, incidence, or discontinuations, or generate causal harm estimates.", "criterion": "Distinguish harm collection, events/persons, exposure/denominators, discontinuation, and nonreporting by product/duration.", "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application — internal adaptation for adverse-event records. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Plan systematic harm collection and follow-up of discontinuations in the same formulation, population, and duration, and report persons/events and denominators separately." }, { "item_id": "N34", "question_type": "Nutrition and risk examples", "question": "Were the meanings of 5 mg/day, 10 g/day, and the absence of an established UL distinguished?", "needed": "Relevant sections of official nutrition/excess-intake risk documents and safety data for the actual formulation, population, and exposure.", "role": "Supplementary; required for defining safety scope", "role_reason": "Needed to avoid mistaking official examples and an unestablished upper limit for an individual therapeutic dose or unlimited safety.", "application_exception": "The official web document was not newly read in this review, and the original numbers are not converted into toxicity thresholds or efficacious doses.", "criterion": "Distinguish nutritional reference values, gastrointestinal harm examples, and the absence of an established upper intake level from therapeutic doses, toxicity thresholds, or safety guarantees.", "basis": "M19 §19.1.2–19.2.4; internal application; Chamgap's own interpretation boundaries. M19 principles are referenced; no formal causality tool was applied; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is internally designed — internal adaptation for nutrition and risk examples. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Compare the nature of official reference values and examples of harm-associated exposure by formulation, population, and duration, keeping them separate from personal recommendations." }, { "item_id": "N35", "question_type": "Long-term use and vulnerable groups", "question": "Were safety gaps for high doses, special populations, and interactions retained?", "needed": "Data on long-term use/special populations, underlying diseases, concomitant medications, interactions, and discontinuation/recovery for single-active-ingredient formulations.", "role": "Supplementary; required for the relevant safety expansion", "role_reason": "Needed to avoid generalizing limited product observations or a statement of no known interactions into safety for all populations.", "application_exception": "Do not impose every rare-harm study on the narrow lesion-efficacy question, and do not newly assess individual causality, risk, or discontinuation/rechallenge.", "criterion": "Distinguish short-term product observations from the scope of long-term single-active-ingredient use, pregnancy/lactation, children, liver/kidney disease, and concomitant medications.", "basis": "M19 §19.1.2–19.2.4; internal application; design considerations in M19 §19.2.2–19.2.4; detailed recording of confounding is internally designed — internal adaptation for long-term use and vulnerable groups. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Review designs for harm follow-up that distinguish populations, durations, and concomitant exposures, and report information gaps for vulnerable groups separately." }, { "item_id": "N36", "question_type": "Search and update scope", "question": "Was the lack of direct verification kept from being extended to worldwide absence or a current search?", "needed": "Original search/selection ledger, registration/access records, correction/retraction information, and current original-text versions.", "role": "Required", "role_reason": "Needed to avoid guaranteeing an absence of studies in a current exhaustive search from a direct evidence gap within the recorded search scope.", "application_exception": "No searches, external full-text reading, or registration/API lookups were performed in this review. Failures described in the manuscript are not retroactively relabeled as events in this review.", "criterion": "Specify the original reference date, search/access limitations at that time, the scope of the current preservation conversion, and links to individual updates.", "basis": "M04 §4.5, §4.6.3; limitations on the current material conversion reflect the user's scope and internal design; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed — internal adaptation for search and update scope. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "If new material becomes available within an authorized scope, distinguish search/access events, additions of evidence, and revisions of conditions, and re-review the linked rows." }, { "item_id": "N37", "question_type": "Preservation of the original judgment", "question": "Were the scope of the original ?, empty values, axes, and direct-human-evidence flags preserved?", "needed": "The gate scope of the original grade/score, axes, and assessment_profile, together with self-review and publication metadata.", "role": "Required (preservation contract)", "role_reason": "Needed to avoid turning unverified direct eligibility into absence of all human evidence, a score of 0, no effect, or new clinical certification.", "application_exception": "Do not inherit C from an adjacent product or C from legacy 028, and do not use the original self-review or grade_revalidated as independent certification in this review.", "criterion": "Preserve the original ?/empty score, B/P, unscored empty values, and flags restricted to direct eligibility without a new judgment.", "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed; M04 §4.5, §4.6.3; limitations on the current material conversion reflect the user's scope and internal design — internal adaptation for preservation of the original judgment. This is not official methodological certification.", "condition_origin": "Case-specific development conditions designed with knowledge of the current original content. This is not blinded validation or preregistration.", "proposed_research": "Compare the preserved original text and display values, and treat only data/table-conversion errors as separate correction events." } ], "language": "en", "translation_date": "2026-11-02" }