{
  "schema_version": "chamgap-public-criteria-1.0",
  "title": "Oral berberine alone or combined with letrozole × Cumulative live birth in infertility associated with PCOS",
  "language": "en",
  "translation_date": "2026-10-27",
  "criteria_version": "1.0",
  "criteria_date": "2026-10-05",
  "condition_origin": "Chamgap's own application conditions",
  "method_sources": [
    {
      "id": "M03",
      "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08",
      "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-03",
      "section": "§3.1, §3.2.1–3.2.3, MECIR C5/C7/C13",
      "official_principle": "Clearly record the question, eligibility conditions and reasons for changes; distinguish intervention variants.",
      "review_level": "Retained method-application records were reused. External originals were not reread and method content was not reassessed."
    },
    {
      "id": "M04",
      "version": "Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03",
      "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-04",
      "section": "§4.5, §4.6.1–4.6.3, MECIR C42",
      "official_principle": "Link studies and reports separately; do not omit studies solely because results are unreported.",
      "review_level": "Retained method-application records were reused. External originals were not reread and method content was not reassessed."
    },
    {
      "id": "M08",
      "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10",
      "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-08",
      "section": "§8.1–8.2.3, Table 8.2.a",
      "official_principle": "Fix the result and effect of interest when examining randomization, deviations, missingness, measurement and selective reporting.",
      "review_level": "Retained method-application records were reused. External originals were not reread and method content was not reassessed."
    },
    {
      "id": "M15",
      "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08",
      "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-15",
      "section": "§15.2.4, §15.3.1–15.3.3",
      "official_principle": "Distinguish effect estimates, intervals, importance and applicability. Sample size alone does not determine precision.",
      "review_level": "Retained method-application records were reused. External originals were not reread and method content was not reassessed."
    },
    {
      "id": "M19",
      "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10",
      "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-19",
      "section": "§19.1.2, §19.2.1–19.2.4",
      "official_principle": "Harm questions may require different designs, populations and follow-up from efficacy questions. Case reports do not establish incidence.",
      "review_level": "Retained method-application records were reused. External originals were not reread and method content was not reassessed."
    }
  ],
  "status_dictionary": {
    "Met": "The row’s narrow record, attribution, boundary or actual fact was checked. This does not certify efficacy, precision or safety.",
    "Partly verified": "Some required information is available, but actual exposure, definitions, denominators or other necessary material remain missing.",
    "Unverified": "The criterion cannot be established within the retained scope. This does not mean 0 effect, 0 studies or failed access.",
    "Not applicable": "The condition has no applicable subject within the current retained set and narrow question. This does not replace a material gap or unread status.",
    "Not reported": "Limited to the particular material or section actually read. It is not extended to the entirety of an unread external paper.",
    "Review incomplete": "A status for external original-material comparison not yet performed, distinguished from review of locally retained content."
  },
  "requirements": [
    {
      "item_id": "N01",
      "question_type": "Evidence condition",
      "question": "Is the question fixed to cumulative live birth with berberine alone versus letrozole alone?",
      "needed": "Linked records of the original claim, intervention, comparator and derived-comparison boundary",
      "role": "Required",
      "role_reason": "Separating a treatment-replacement question from an add-on question prevents monotherapy results from being read as combination effects.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Retain the original claim and explicitly identify berberine alone versus letrozole alone as a derived comparison.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If the boundary changes, redefine the actual intervention/comparator combination and review it in a separate version."
    },
    {
      "item_id": "N02",
      "question_type": "Evidence condition",
      "question": "Are the two monotherapy arms and the roles of double-dummy placebos distinguished in the retained account?",
      "needed": "Records of active ingredients, placebo allocation and actual comparator roles in the 3 arms",
      "role": "Required",
      "role_reason": "Changing the active letrozole comparator into a no-treatment comparator changes the meaning of the replacement strategy.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Select berberine alone and letrozole alone; do not read the double dummy as a pure no-treatment placebo arm.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If the full protocol is obtained, compare active/placebo allocation by arm and keep different strategies distinct."
    },
    {
      "item_id": "N03",
      "question_type": "Evidence condition",
      "question": "Are the trial berberine’s exact salt form, source, product and standardization established?",
      "needed": "Berberine product name, manufacturer, salt form, batch and standardization material",
      "role": "Required",
      "role_reason": "Product matching prevents monotherapy replacement results from being transferred to arbitrary berberine hydrochloride or plant products.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish the exact chemical form, product identifier, source, content standardization and application to the selected arm.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If original product material is obtained, compare composition and standardization and review unmatched products as separate questions."
    },
    {
      "item_id": "N04",
      "question_type": "Evidence condition",
      "question": "Are the planned oral berberine monotherapy dose, actual intake and adherence established?",
      "needed": "Arm-specific prescriptions, adherence, actual daily doses and discontinuation records",
      "role": "Required",
      "role_reason": "It is necessary to know whether actual exposure under the monotherapy strategy matched the planned dose.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Distinguish planned oral 1.5 g/day from actual intake, adherence, discontinuation and changes.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Use dosing records to distinguish planned from actual exposure and compare the effects of deviations with the predefined analysis."
    },
    {
      "item_id": "N05",
      "question_type": "Evidence condition",
      "question": "Are the active letrozole comparator’s planned dosing, escalation and actual administration established?",
      "needed": "Comparator-arm letrozole prescriptions by cycle, dose escalation and actual intake records",
      "role": "Required",
      "role_reason": "Unclear actual exposure to the active replacement comparator limits interpretation of the monotherapy-strategy comparison.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish planned comparator letrozole 2.5 mg on cycle days 3–7, increasing to 5 mg if needed, alongside actual escalation and administration.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare actual comparator dosing by cycle with the planned escalation criteria."
    },
    {
      "item_id": "N06",
      "question_type": "Evidence condition",
      "question": "Are the actual population and Rotterdam PCOS/infertility eligibility criteria sufficiently established for the selected comparison?",
      "needed": "Diagnosis, age, infertility duration, inclusion/exclusion criteria and arm-specific population characteristics",
      "role": "Required",
      "role_reason": "Population conditions prevent extension of this monotherapy comparison to other infertility causes or women generally.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish the description of infertile women with Rotterdam PCOS and the detailed diagnostic, age and eligibility criteria.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If eligibility criteria and baseline tables are obtained, compare the target population with the actual trial population."
    },
    {
      "item_id": "N07",
      "question_type": "Evidence condition",
      "question": "Are baseline infertility causes, prior treatment and arm-specific prognostic characteristics established?",
      "needed": "Arm-specific baseline tables, investigations of infertility causes, prior treatment and medical histories",
      "role": "Required",
      "role_reason": "Actual data are needed to examine baseline prognostic balance when comparing the monotherapy replacement strategies.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish prognosis in the selected arms, including male/tubal factors, baseline ovulatory/metabolic status and previous treatment.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare baseline material with planned handling of prognostic variables and actual balance."
    },
    {
      "item_id": "N08",
      "question_type": "Evidence condition",
      "question": "Are actual random-sequence generation and implementation of the allocation ratio established in this multicenter trial?",
      "needed": "Random-sequence generation, stratification, site-specific allocation procedures and CONSORT flow material",
      "role": "Required",
      "role_reason": "More than the allocation description is needed to assess selection bias in the two monotherapy arms.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish not only the multicenter RCT and 1:1:1 description but also sequence generation, stratification and site-specific implementation.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare the protocol and allocation procedures to examine implementation of randomization for the selected arms."
    },
    {
      "item_id": "N09",
      "question_type": "Evidence condition",
      "question": "Are allocation concealment and recruitment procedures established for the two selected arms?",
      "needed": "Allocation concealment, enrollment timing, recruitment sequence and actual implementation material",
      "role": "Required",
      "role_reason": "Recruitment bias from predictable allocation also needs examination in an active-treatment replacement comparison.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish recruitment before allocation disclosure, concealment methods and actual implementation in the selected arms.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Obtain allocation/enrollment documents to examine concealment procedures in relation to recruitment timing."
    },
    {
      "item_id": "N10",
      "question_type": "Evidence condition",
      "question": "Are actual double-dummy blinding and the independence of live-birth ascertainment established?",
      "needed": "Placebo matching, maintenance/breaking of blinding, outcome assessors and verification procedures",
      "role": "Required",
      "role_reason": "These conditions examine dosing, subsequent treatment and ascertainment deviations in the comparison of two different active drugs.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish the double-blind/double-dummy description, placebo matching, unblinding or guessability and birth-ascertainment procedures.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare protocol and ascertainment documents to examine implementation of blinding and independence of outcome assessment."
    },
    {
      "item_id": "N11",
      "question_type": "Evidence condition",
      "question": "Are concomitant/rescue treatments and deviations established in the two monotherapy-strategy arms?",
      "needed": "Arm-specific concomitant/rescue treatment, crossover, other infertility treatment and reasons for discontinuation",
      "role": "Required",
      "role_reason": "Different subsequent treatments can prevent attribution solely to replacement with the monotherapy drug.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish actual concomitant/rescue and other infertility treatments and differences between the two monotherapy arms.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Reconstruct arm-specific treatment pathways to examine the definition of the effect of interest and appropriate handling of deviations."
    },
    {
      "item_id": "N12",
      "question_type": "Evidence condition",
      "question": "Are the maximum 6-month plan, actual individual treatment/cycle counts and exposure after pregnancy established?",
      "needed": "Arm-specific actual treatment duration, cycle counts, discontinuation timing and dosing after pregnancy",
      "role": "Required",
      "role_reason": "Treatment duration under the monotherapy strategy must not be changed into the total length of pregnancy follow-up.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Distinguish the maximum 6-month plan from actual treatment duration, ovulatory cycle counts, discontinuation and exposure after pregnancy confirmation.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Distinguish the treatment calendar from pregnancy follow-up and examine actual exposure duration and discontinuation pathways."
    },
    {
      "item_id": "N13",
      "question_type": "Evidence condition",
      "question": "Are the length, end and completeness of pregnancy follow-up for live-birth ascertainment established?",
      "needed": "Arm-specific pregnancy/birth follow-up schedules, last contact, follow-up end and completeness",
      "role": "Required",
      "role_reason": "The observation window for birth outcomes in the monotherapy comparison can differ from treatment duration.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Distinguish treatment end from follow-up after pregnancy through birth and establish arm-specific follow-up start, end and completeness.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare the observation window from pregnancy onset to birth confirmation with incomplete follow-up."
    },
    {
      "item_id": "N14",
      "question_type": "Evidence condition",
      "question": "Are the event definition, cumulative method and measurement unit of cumulative live birth sufficiently established?",
      "needed": "Endpoint definition, birth-verification procedures, cycle-accumulation rules and handling of multiple/repeated births",
      "role": "Required",
      "role_reason": "Ovulation, pregnancy or infant counts must not be substituted for cumulative live birth per woman in the monotherapy comparison.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish the cumulative-live-birth label, gestational-age criteria, woman/infant unit, accumulation across cycles, multiple-birth handling and verification procedures.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Obtain endpoint specifications to examine consistency of woman, cycle and infant units with cumulative counting."
    },
    {
      "item_id": "N15",
      "question_type": "Evidence condition",
      "question": "Are the original reported rates of 22% versus 36% accurately attributed to the monotherapy comparison?",
      "needed": "Attribution records linking each arm’s reported rate, name, original statement and result location",
      "role": "Required",
      "role_reason": "This condition preserves observations for the monotherapy comparison without confusing reported rates across the three arms.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Link berberine 22% and letrozole 36% to the selected comparison and retain combination 34% as original context.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "When new reports are obtained, first verify arm names for the same endpoint, denominator and time, then compare with existing attribution."
    },
    {
      "item_id": "N16",
      "question_type": "Evidence condition",
      "question": "Are randomized, analyzed, completed and endpoint-observed denominators established for the two selected arms?",
      "needed": "CONSORT counts, analysis populations, birth-endpoint denominators and missing-data flow for the two selected arms",
      "role": "Required",
      "role_reason": "Denominators for the two monotherapy arms must not be replaced by the overall 644 or by 644/3.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Distinguish the overall 644-participant allocation description from each selected arm’s randomized, analyzed, completed and endpoint-observed numbers.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare definitions of each denominator to distinguish overall allocation from the endpoint-analysis population."
    },
    {
      "item_id": "N17",
      "question_type": "Evidence condition",
      "question": "Are live-birth event counts and person/infant/cycle units established for the two selected arms?",
      "needed": "Original live-birth events, denominators, units and handling of repeated/multiple births",
      "role": "Required",
      "role_reason": "Reported percentages alone cannot generate birth events or women for the monotherapy arms.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish original event counts and the person/infant/cycle units of their denominators without back-calculating reported rates.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Obtain original result tables to examine the relation between events and person/cycle denominators."
    },
    {
      "item_id": "N18",
      "question_type": "Evidence condition",
      "question": "Are the effect of interest, ITT/PP and handling of intercurrent events established for the monotherapy-strategy comparison?",
      "needed": "Estimand specifications, ITT/PP populations and plans/results for intercurrent events and missing data",
      "role": "Required",
      "role_reason": "Replacement-strategy effects and effects of actual monotherapy intake can differ.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Define whether the effect concerns assigned monotherapy strategies or actual intake and establish handling of pregnancy, discontinuation, rescue treatment, missing data and ITT/PP.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "After establishing the estimand and analysis populations, examine how pregnancy, discontinuation and rescue treatment enter the definition."
    },
    {
      "item_id": "N19",
      "question_type": "Evidence condition",
      "question": "Are the formal estimator, method, P and confidence interval for the selected between-arm effect established?",
      "needed": "Original between-arm effect estimates, model, P, confidence interval, denominator and endpoint time",
      "role": "Required",
      "role_reason": "Reported monotherapy rates must be distinguished from formal replacement-effect precision.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish original estimates, uncertainty, denominator and time from an appropriate unadjusted or adjusted between-arm model.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare original analysis tables and the SAP to establish comparison estimates and precision. Do not exclude an unadjusted analysis solely because it is unadjusted."
    },
    {
      "item_id": "N20",
      "question_type": "Evidence condition",
      "question": "Are clinical importance and interpretation criteria for superiority, noninferiority or equivalence established for the selected comparison?",
      "needed": "Hypotheses, clinical-importance/noninferiority margins, effect confidence intervals and interpretation plans",
      "role": "Required",
      "role_reason": "The unfavorable monotherapy direction and the magnitude/precision of clinically important differences require separate examination.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Compare prespecified hypotheses and clinical-importance criteria with the corresponding confidence interval; do not convert nonsignificance or original no-benefit wording into equivalence.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Establish original hypotheses and margins, then examine how confidence intervals address clinically important differences."
    },
    {
      "item_id": "N21",
      "question_type": "Evidence condition",
      "question": "Are losses, missing data, incomplete birth follow-up and the effects of their handling established for the selected arms?",
      "needed": "Arm-specific losses, missing/incomplete pregnancy or birth follow-up, reasons, handling and sensitivity material",
      "role": "Required",
      "role_reason": "Reported monotherapy-strategy rates can depend on handling of women not followed up.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish arm-specific missing data, reasons for loss, unconfirmed births, analysis handling and sensitivity analyses.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Examine consistency between missing-data flow and planned handling and establish the scope of original sensitivity analyses."
    },
    {
      "item_id": "N22",
      "question_type": "Evidence condition",
      "question": "Is consistency of preregistration, protocol and SAP with actual reporting established for the selected comparison?",
      "needed": "Actual ChiCTR/WHO registration versions, change histories, protocol, SAP and original result tables",
      "role": "Required",
      "role_reason": "More than a registration number is needed to establish that this monotherapy comparison and analysis were prespecified.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Use the ChiCTR identifier as a lead to compare actual registration versions, timing, selected arms, endpoints and analysis plans with the original report.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If registration and SAP are obtained, compare registration timing, hypotheses, arms, endpoints and analyses with reporting."
    },
    {
      "item_id": "N23",
      "question_type": "Evidence condition",
      "question": "Are multiplicity handling and hypothesis hierarchy established for the two derived comparisons in the 3-arm trial?",
      "needed": "3-arm hypothesis hierarchy, multiplicity handling, comparison-specific SAP and reported results",
      "role": "Required",
      "role_reason": "Splitting a 3-arm trial into two sheets still requires establishing the monotherapy comparison’s hypothesis hierarchy.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish prespecified hierarchy and multiplicity handling for the monotherapy/add-on comparisons and examine reporting selection.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare the original SAP with complete results to examine comparison selection and multiplicity handling."
    },
    {
      "item_id": "N24",
      "question_type": "Evidence condition",
      "question": "Are both the unfavorable monotherapy direction and the historical no-added-benefit statement retained?",
      "needed": "Preservation records of original results, counterviews, original assessment, axes and correction history",
      "role": "Required",
      "role_reason": "The unfavorable monotherapy observation must not be covered over by metabolic possibilities or add-on results.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Retain all three-arm rates, original conclusions, D 34 and all axes without alteration rather than selecting favorable results only.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If subsequent reports become available, compare favorable, unfavorable and no-benefit material under the same attribution rules and record changes as separate events."
    },
    {
      "item_id": "N25",
      "question_type": "Evidence condition",
      "question": "Are the ChiCTR link, exclusion of the wrong NCT and original unverified registration-field wording kept distinct?",
      "needed": "Linked records of PMID, DOI, ChiCTR, excluded NCT and the original registration field",
      "role": "Required",
      "role_reason": "These records prevent the monotherapy trial’s identity from being changed to an incorrect unrelated registration.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Distinguish ChiCTR-TRC-09000376/PMID/DOI from the excluded NCT01116167 and retain the original registration field’s “not established” wording.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If actual registration material is obtained, compare identifiers, population, 3 arms and endpoints and record discrepancies as separate correction events."
    },
    {
      "item_id": "N26",
      "question_type": "Evidence condition",
      "question": "Is it explicit that the two derived sheets concern the same 3-arm trial and shared letrozole arm?",
      "needed": "Relationship records linking one study family, two comparisons, the shared control and report identifiers",
      "role": "Required",
      "role_reason": "Displaying monotherapy and add-on comparisons as separate questions must not double-count one study’s control arm.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Group the same PMID/DOI/ChiCTR into one study family and do not add the two sheets/shared control as independent trials or independent participants.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare report populations, recruitment and identifiers to link the same family and duplicated controls."
    },
    {
      "item_id": "N27",
      "question_type": "Evidence condition",
      "question": "Are independent replication of the same question and the scope of access established?",
      "needed": "Identities, reports, search scope and original material for independently recruited studies",
      "role": "Required",
      "role_reason": "Splitting the same 3-arm report into two sheets does not establish replication of the monotherapy replacement comparison.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Establish separately recruited studies of the same population, exposure, comparator and live-birth endpoint and the actual reading/search scope.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If new-material review is authorized, assess question-specific eligibility and compare independent recruitment and report overlap."
    },
    {
      "item_id": "N28",
      "question_type": "Evidence condition",
      "question": "Is there an applicable set for examining heterogeneity between distinct independent trials in the current retained material?",
      "needed": "Differences in populations, interventions, endpoints and analyses if additional independent families are established",
      "role": "Supplementary; required when synthesizing multiple independent study families",
      "role_reason": "The one family retained for the monotherapy comparison is not synthesized as multiple independent trials.",
      "application_exception": "With only one family in the current retained set, between-trial heterogeneity is not applicable. Differences between comparisons within the study and dependence from the shared control remain subject to examination.",
      "criterion": "Do not treat two comparisons in the same study family as between-trial heterogeneity; examine differences between trials when another eligible family is established.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If a separate family is obtained, compare question matching and design, population and estimator differences to examine whether synthesis is appropriate."
    },
    {
      "item_id": "N29",
      "question_type": "Evidence condition",
      "question": "Are monotherapy dose response, longer-term effects and subgroup effects beyond the trial dose/duration established?",
      "needed": "Direct comparisons and interaction data for additional doses, durations, products and subgroups",
      "role": "Supplementary; required when extending to other doses, durations or subgroups",
      "role_reason": "The berberine 1.5 g/day monotherapy trial is not extended to replacement effects for all doses, forms and long-term exposures.",
      "application_exception": "The narrow selected comparison does not always require evidence for every dose. Direct evidence is needed only for the extension being considered.",
      "criterion": "Establish extensions beyond actual trial dose, duration and population using direct material and prespecified subgroup/interaction evidence.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "When an extension question is needed, review its material as a separate question; do not read simple subgroup differences as interactions."
    },
    {
      "item_id": "N30",
      "question_type": "Evidence condition",
      "question": "Is the boundary between live birth and ovulation, pregnancy, metabolic or weight outcomes maintained?",
      "needed": "Records of endpoint hierarchy and attribution boundaries for other outcomes",
      "role": "Required",
      "role_reason": "Birth results in the monotherapy arm must not be replaced by other intermediate outcomes.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Fix the selected comparison to cumulative live birth; do not replace it with possible effects on ovulation, pregnancy rates, insulin or weight.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If material on other outcomes is obtained, review those questions separately and interpret their relationship to live birth only where direct linking evidence exists."
    },
    {
      "item_id": "N31",
      "question_type": "Evidence condition",
      "question": "Are funding, product support, author relationships and conflicts specifically established?",
      "needed": "Funding bodies, research funding, berberine/letrozole supply, author relationships and conflict declarations",
      "role": "Required",
      "role_reason": "Funding/product influence on monotherapy replacement results must be examined through actual arm-specific support details.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Distinguish the public-research-network description from actual supporting institutions, product supply, author relationships and conflict declarations.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "Compare original support and conflict statements to establish research funding, product provision and author relationships separately."
    },
    {
      "item_id": "N32",
      "question_type": "Evidence condition",
      "question": "Are actual maternal, pregnancy and fetal/neonatal harm collection and results established for the selected comparison?",
      "needed": "Arm-specific maternal/pregnancy/fetal/neonatal harm definitions, active collection, event/person denominators, timing, exposure, discontinuation and concomitant-treatment material",
      "role": "Supplementary; required when explaining pregnancy safety or personal-use decisions",
      "role_reason": "The monotherapy live-birth comparison alone cannot establish pregnancy safety, so separate harm information is needed.",
      "application_exception": "The principal question concerns live-birth efficacy. Harm incidence is not imposed as an efficacy condition, while safety explanation and personal application require separate direct material.",
      "criterion": "Establish arm-specific harm definitions, collection methods, exposure/follow-up timing, event/person denominators, discontinuations, concomitant treatment and actual results.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If original safety material is obtained, compare harm definitions, collection, follow-up, denominators and discontinuation/concomitant treatment to distinguish signals from comparative risks."
    },
    {
      "item_id": "N33",
      "question_type": "Evidence condition",
      "question": "Are historical warnings, actual trial harms and personal-use decisions kept distinct?",
      "needed": "Records distinguishing the roles of original safety warnings and actual event material",
      "role": "Required",
      "role_reason": "The monotherapy strategy’s live-birth result and the original pregnancy warning have different roles in the evidence.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Retain original warnings without promoting them to actual risk estimates, established causation, long-term safety or new personal dosing instructions.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If original safety material is added, establish the warning’s basis, population and events and examine these separately from comparative risk."
    },
    {
      "item_id": "N34",
      "question_type": "Evidence condition",
      "question": "Are the original review date, correction date, current sheet-review date and search/reading limits distinguished?",
      "needed": "Original review date, correction date, current review date, search scope and actual access records",
      "role": "Required",
      "role_reason": "Currency of the monotherapy comparison cannot be established by changing the original review date into a new search date.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Retain original review and correction dates, do not infer absent cutoff/individual access dates, and distinguish whether current new searches or external reading occurred.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "When new evidence updating is authorized, record search dates, scope and access events as new records without backdating historical dates."
    },
    {
      "item_id": "N35",
      "question_type": "Evidence condition",
      "question": "Are English correction history, remaining generic wording and original null/empty values retained?",
      "needed": "Preservation records of original corrections, bilingual fields, empty values, absent fields and types",
      "role": "Required",
      "role_reason": "Generic English wording must not be read as new denominator, confidence-interval or funding facts for the monotherapy comparison.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Do not fill the 1 correction or remaining generic verification wording with specific clinical values; retain empty detailed-claim lists/review notes, original axes and original types.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If a new bilingual correction is needed, establish corresponding original values and the correction event and preserve the entire text before change."
    },
    {
      "item_id": "N36",
      "question_type": "Evidence condition",
      "question": "Are current retained-summary reading, unread external materials and historical matching statements separated by material type?",
      "needed": "Material-specific current acquisition/reading, URL, version, historical access date/level and original-location records",
      "role": "Required",
      "role_reason": "Reading a monotherapy-comparison summary must not be represented as rereading the paper’s full text.",
      "application_exception": "This condition concerns actual material for the selected comparison. Information from another known comparison, a non-live-birth endpoint or a different product does not substitute for it; no arbitrary sample-size threshold is imposed.",
      "criterion": "Distinguish actual reading of retained summaries from current unattempted/unread PubMed, DOI, paper, registration and SAP materials; do not inherit access levels/dates from a containing document.",
      "basis": "Existing method principles distinguish population, active treatment, actual exposure, cumulative live birth, follow-up, denominators, analysis, shared controls, funding and harms. Detailed conditions are Chamgap’s own application.",
      "condition_origin": "These conditions concern cumulative live birth with berberine alone versus letrozole alone and were developed with knowledge of the retained content. They were frozen before application; this does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.",
      "proposed_research": "If external material is actually obtained, verify its own access event, version and original locations and update only the current reading record."
    }
  ]
}