@pikaa-ai/pikaa 0.3.1 → 0.3.4

package/skills/clinical-reports/references/data_presentation.md

@@ -1,92 +0,0 @@
-# Aggregate Data Presentation
-
-Present verified outputs without changing their meaning. Do not calculate a clinical conclusion, select an analysis, or repair source discrepancies.
-
-## Mandatory table metadata
-
-Every table should identify:
-
-- artifact and analysis purpose;
-- data cut and source-output version;
-- analysis population/set;
-- treatment/group labels;
-- denominator for every group and row when it varies;
-- whether a value is a subject count, event count, observation count, or estimate;
-- units, time point/window, and summary statistic;
-- missing, unknown, not assessed, suppressed, or not applicable values;
-- coding dictionary/version/language where applicable;
-- statistical method and multiplicity status only when copied from a verified output;
-- provenance manifest and reviewer status.
-
-## Counts and denominators
-
-- Show `n/N (%)`, not a percentage alone, unless the governing output specifies another form.
-- Require `0 <= n <= N` and `N > 0`.
-- Recalculate only for consistency checking; do not silently replace the reported percentage.
-- State the rounding rule and tolerance.
-- Do not add subgroup percentages when the subgroup denominator is unknown.
-- Do not infer that denominators are randomized, treated, evaluable, or safety populations.
-- Keep event counts distinct from subjects affected; event counts can exceed the number of subjects.
-- Do not sum non-mutually-exclusive categories.
-
-## Dates and time
-
-- Use ISO 8601 in structured manifests.
-- Preserve source timezone and precision.
-- Distinguish event date, collection date, database cut, report date, and verification date.
-- Flag start-after-end and conflicting dates.
-- Do not impute a missing day, month, timezone, or chronology.
-- For de-identified case reports, use an authorized relative timeline; do not distort intervals.
-
-## Units and precision
-
-- Preserve source units.
-- Require a unit for every dimensional quantity.
-- Use one verified unit per comparable series or expose the mismatch.
-- Do not convert or normalize without an authorized traceable conversion rule.
-- Preserve clinically meaningful precision; do not create extra significant digits.
-- Identify SD, SE, CI, IQR, range, and denominator explicitly.
-
-## Missing and suppressed values
-
-Keep these states distinct:
-
-- `missing`;
-- `not_collected`;
-- `not_assessed`;
-- `unknown`;
-- `not_applicable`;
-- `suppressed_for_privacy`;
-- `zero`.
-
-Never convert a blank to zero. State small-cell suppression rules and ensure totals or complementary cells do not reveal suppressed values.
-
-## Adverse-event tables
-
-For term-level aggregate tables:
-
-- state MedDRA version and language;
-- state analysis set and denominator;
-- state counting rule from the verified SAP/output;
-- show subjects affected and event count separately;
-- do not add p-values or causal labels;
-- do not interpret between-group differences;
-- preserve threshold rules exactly;
-- have safety and statistical reviewers verify deduplication, hierarchy, and population.
-
-## Figures
-
-No figure is mandatory. Create one only when requested, supported by verified aggregate data, allowed by the target guidance, and reviewable without external image generation.
-
-A CONSORT flow diagram is part of CONSORT 2025 reporting, but every count and reason must come from verified trial outputs. A missing count remains missing; do not create a decorative or inferred diagram.
-
-## Deterministic consistency check
-
-`consistency_checker.py` can inspect:
-
-- ISO date and range ordering;
-- unit-label consistency;
-- `n/N (%)` arithmetic;
-- component-total arithmetic.
-
-It reports mismatches and review needs. It does not change the input, choose the correct source, or validate clinical/statistical meaning.

package/skills/clinical-reports/references/diagnostic_reports_standards.md

@@ -1,76 +0,0 @@
-# Diagnostic-Report Scaffolds
-
-These assets are structured field maps for authorized clinical services. They do not interpret data or produce a report suitable for patient care.
-
-## Radiology
-
-The ACR **Practice Parameter for Communication of Diagnostic Imaging Findings**, revised 2025 (Resolution 9), addresses diagnostic imaging reports, final-report principles, preliminary reports, nonroutine communication, informal communication, and organizational communication policies.
-
-Use `assets/radiology_report_template.json` only to map verified facts such as:
-
-- examination identity and status;
-- clinical indication as supplied;
-- technique and documented limitations;
-- comparison-source references;
-- findings and impression authored by the qualified interpreting professional;
-- nonroutine-communication record references;
-- amendments/corrections and report version.
-
-Do not:
-
-- inspect or interpret images;
-- generate normal findings, pertinent negatives, differential diagnoses, urgency, follow-up, or management recommendations;
-- select BI-RADS, LI-RADS, Lung-RADS, PI-RADS, or another category;
-- infer that a preliminary report is final;
-- initiate, simulate, or document a communication that did not occur.
-
-The responsible radiologist and organization control report content, communication, correction, and signature.
-
-## Pathology
-
-CAP publishes and updates organ- and specimen-specific Cancer Protocols. The CAP template page showed protocol updates on 17 June 2026 and a Breast DCIS correction on 24 June 2026 when checked. Protocol versions and required/core or conditional elements can change.
-
-Use `assets/pathology_report_template.json` only after a qualified pathologist selects:
-
-- exact organ/site and specimen/procedure;
-- current CAP protocol title and version, if applicable;
-- applicable biomarker protocol and staging edition;
-- local laboratory/reporting requirements.
-
-For CAP synoptic reporting within its scope, core and conditionally required data elements are represented as data-element/response pairs; applicability depends on the exact current protocol.
-
-Do not:
-
-- generate a gross or microscopic observation;
-- determine diagnosis, grade, stage, margin status, biomarker interpretation, or adequacy;
-- apply a generic cancer checklist in place of the current exact protocol;
-- convert `cannot be determined` or `not applicable` into a definitive value;
-- create a signature or final diagnosis.
-
-## Laboratory
-
-For applicable US nonwaived testing, 42 CFR 493.1291 addresses accurate and timely transmission, required report information, referral-laboratory handling, accessibility, and corrected reports. The exact regulation and laboratory policy control.
-
-Use `assets/lab_report_template.json` only to map results already released by the performing laboratory or verified source system. Preserve:
-
-- report status and version;
-- performing laboratory/source-system reference;
-- specimen and test identifiers held in the authorized system, not copied into examples;
-- result, units, reference interval, flags, method, and comments exactly as released;
-- correction link to both original and corrected reports;
-- documented notification reference when one exists.
-
-Do not:
-
-- calculate, normalize, convert, interpret, flag, or suppress a patient result;
-- supply a reference interval or “critical” threshold;
-- infer specimen adequacy;
-- recommend follow-up or treatment;
-- alter a referral laboratory’s result or interpretation;
-- release or sign a report.
-
-## Privacy and record integrity
-
-Operational diagnostic reports often require identifiers for positive patient matching. This skill does not process those production records. It accepts only synthetic, de-identified, or aggregate manifests. Use institution-controlled systems for real clinical records and follow applicable access, retention, correction, audit, and disclosure procedures.
-
-Every draft scaffold must remain `DRAFT_NOT_FOR_CLINICAL_USE` until the responsible licensed service reviews and completes it in its authorized system.

package/skills/clinical-reports/references/medical_terminology.md

@@ -1,84 +0,0 @@
-# Versioned Terminology and Schema Checks
-
-Terminology selection and coding are clinical/regulatory tasks. The local checker validates manifest shape and code syntax; it does not confirm that a code exists, is current, matches a display, or is clinically appropriate.
-
-## Required manifest fields
-
-For every coded item record:
-
-- `system`: controlled system name;
-- `system_uri`: canonical identifier supplied by the implementing organization;
-- `code`;
-- `display`;
-- `version`;
-- `language`;
-- `source_fact_id`;
-- `coding_status`: `verified_by_qualified_reviewer` or `unverified`;
-- `verified_by_role` and `verified_at` when verified.
-
-Do not infer a code from narrative text.
-
-## MedDRA
-
-- ICH developed MedDRA for regulatory information about human medical products.
-- MedDRA 29.0 was released in March 2026, with a transition date of 4 May 2026.
-- MedDRA uses a multiaxial hierarchy and version-specific currency/relationships.
-- State exact version and language.
-- Use the study/sponsor-authorized version, official licensed files, and current Points to Consider.
-- Do not assume the newest release is the required release.
-
-The aggregate adverse-event formatter accepts SOC and PT labels as supplied and does not validate hierarchy, codes, or coding quality.
-
-## LOINC
-
-LOINC identifies health observations, measurements, and documents. LOINC 2.82 was released 24 February 2026 and was current when checked.
-
-- A valid-looking `number-checkdigit` string is only syntactic evidence.
-- The method, property, timing, system/specimen, scale, and version can affect meaning.
-- Verify against the official release or authorized terminology service.
-- Review the LOINC license and third-party content terms.
-
-## SNOMED CT
-
-SNOMED CT concept identifiers are not clinically validated by their numeric shape.
-
-- Use the applicable international edition, national extension, and effective date.
-- Verify concept activity, module, description, and reference-set membership.
-- Comply with SNOMED International and national licensing/distribution requirements.
-- Do not embed or redistribute licensed terminology content through these assets.
-
-## ICD-10-CM
-
-ICD-10-CM changes by fiscal-year release and may require encounter, laterality, or placeholder characters.
-
-- Record the exact release and applicable jurisdiction.
-- Verify with official CDC/CMS files and coding guidance.
-- A regex match cannot establish billability, specificity, sequencing, or clinical correctness.
-- This skill does not support billing or reimbursement decisions.
-
-## UCUM and units
-
-Record the original unit exactly and, when an organization uses UCUM, record the verified UCUM expression separately. Do not automatically convert units in a report draft.
-
-Any conversion must have:
-
-- an authorized rule and version;
-- original value/unit;
-- converted value/unit;
-- precision/rounding rule;
-- source-fact and reviewer traceability.
-
-The consistency checker flags missing or inconsistent unit labels but performs no clinical conversion.
-
-## Optional local dictionary
-
-`terminology_validator.py --dictionary <file.json>` can compare code/display/version tuples with a caller-supplied local dictionary. The dictionary must be an authorized bounded JSON file.
-
-A match means only “matched this supplied dictionary.” It does not prove:
-
-- the dictionary is official, complete, current, or licensed for the use;
-- the chosen code is appropriate;
-- the clinical statement is true;
-- the report is compliant or ready for release.
-
-Without a dictionary, the strongest result is `SCHEMA_VALID_SYNTAX_ONLY_REVIEW_REQUIRED`.

package/skills/clinical-reports/references/privacy_and_deidentification.md

@@ -1,84 +0,0 @@
-# Privacy and De-identification
-
-This reference documents a review process. It is not legal advice, a technical de-identification service, or evidence of HIPAA compliance.
-
-## HHS framework
-
-HHS guidance under 45 CFR 164.514(b) describes two methods:
-
-1. **Expert Determination** — a person with appropriate knowledge and experience applies generally accepted statistical and scientific principles and documents that re-identification risk is very small under the anticipated conditions.
-2. **Safe Harbor** — specified identifiers are removed and the covered entity has no actual knowledge that remaining information could identify an individual.
-
-A local script cannot perform Expert Determination, establish “no actual knowledge,” or decide whether an organization is a covered entity or business associate.
-
-## Safe Harbor identifier categories
-
-The responsible privacy professional must review the exact regulation and HHS guidance. The categories include:
-
-1. names;
-2. geographic subdivisions smaller than a state, subject to the specific ZIP-code rule;
-3. date elements more specific than year directly related to an individual, plus the age rule for persons over 89;
-4. telephone numbers;
-5. fax numbers;
-6. email addresses;
-7. Social Security numbers;
-8. medical record numbers;
-9. health-plan beneficiary numbers;
-10. account numbers;
-11. certificate or license numbers;
-12. vehicle identifiers and serial numbers;
-13. device identifiers and serial numbers;
-14. URLs;
-15. IP addresses;
-16. biometric identifiers;
-17. full-face photographs and comparable images;
-18. other unique identifying numbers, characteristics, or codes.
-
-Removal of obvious patterns is insufficient. Initials, partial identifiers, metadata, free text, rare events, small cells, unusual dates, images, and combined quasi-identifiers may still identify a person.
-
-## Minimum necessary
-
-HHS states that covered entities generally take reasonable steps to limit uses, disclosures, and requests for PHI to the minimum necessary for the purpose. HHS also lists exceptions, including certain treatment disclosures, disclosures to the individual, authorized uses/disclosures, uses/disclosures required for HIPAA administration, HHS enforcement, and uses/disclosures required by law.
-
-Do not apply the phrase mechanically. The responsible privacy/legal reviewer determines scope, exceptions, authorization, waiver, limited-data-set rules, and any more protective law or policy.
-
-## Local process
-
-1. Define purpose, recipient, authority, jurisdiction, and data class.
-2. Exclude fields not needed for the purpose.
-3. Keep source records in the authorized system; use field-path references and hashes in the draft workspace.
-4. Select Safe Harbor, Expert Determination, or a documented synthetic/aggregate-data rationale through the responsible reviewer.
-5. Review structured fields, free text, attachments, images, headers, filenames, metadata, and linked data.
-6. Review combinations and small-cell/rare-case risk.
-7. Record actual-knowledge review or Expert Determination documentation as applicable.
-8. Verify access controls, storage, transmission, retention, and deletion under organizational policy.
-9. Obtain privacy/legal/institutional approval for the intended disclosure.
-10. Re-review after every content, recipient, or purpose change.
-
-## What the checklist does
-
-`assets/deidentification_process_checklist.json` and `scripts/check_deidentification.py` verify that required process fields are documented. They deliberately:
-
-- do not scan patient free text;
-- do not output detected identifiers;
-- do not label a document `COMPLIANT`, `SAFE`, or `DEIDENTIFIED`;
-- do not substitute for Expert Determination or legal review;
-- remain blocked when required human review is missing.
-
-The strongest successful result is `PROCESS_DOCUMENTED_REVIEW_REQUIRED`.
-
-## Consent and authorization
-
-Publication consent, research consent, HIPAA authorization, IRB/Privacy Board waiver, and permission to use an image are distinct. Do not infer one from another or generate a stock assertion.
-
-Record only the status and local documentation reference verified by the responsible human. Never store a signed consent form or direct identifier in this skill’s assets, tests, or example manifests.
-
-## Incident handling
-
-If real PHI is unexpectedly present:
-
-1. stop processing;
-2. do not echo, copy, transform, or upload it;
-3. preserve only the minimum operational information needed under policy;
-4. notify the authorized privacy/security contact through the institution’s process;
-5. do not independently determine breach status or notification duties.

package/skills/clinical-reports/references/professional_review.md

@@ -1,78 +0,0 @@
-# Professional, Ethical, and Human Review
-
-## Accountability
-
-Automation may organize verified facts but cannot assume professional accountability. A named, qualified human must review each domain and take responsibility in the authorized system.
-
-The ICMJE Recommendations, updated January 2026, retain four authorship criteria: substantive contribution; drafting or critical review; final approval; and accountability for accuracy and integrity. Writing assistance alone does not confer authorship. An AI system cannot be an author or approve a manuscript.
-
-## Research ethics
-
-The World Medical Association states that the **2024 Declaration of Helsinki** is the current official version. It applies to medical research involving human participants, including identifiable material or data, and emphasizes:
-
-- participant rights and interests over research goals;
-- privacy and confidentiality;
-- scientific validity and a documented protocol;
-- independent research-ethics review;
-- informed consent;
-- transparency and reporting.
-
-This skill neither performs ethics review nor determines whether an activity is research, exempt, or authorized.
-
-## Clinical-record confidentiality
-
-AMA Code of Medical Ethics Opinion 3.3.2 states that information recorded in patient care is confidential regardless of form and identifies access restriction, audit capability, security/integrity, retrieval, sharing, third-party access, and disposition as responsibilities for electronic records.
-
-Use institution-controlled systems for real clinical records. Local draft manifests should contain source locators and hashes rather than PHI.
-
-## Required reviewers by artifact
-
-| Domain | Reviewer responsibility |
-|---|---|
-| Clinical case facts | Qualified clinician verifies facts, uncertainty, chronology, and interpretation |
-| Radiology | Qualified radiologist authors findings/impression and communication status |
-| Pathology | Qualified pathologist selects protocol/version and authors diagnosis |
-| Laboratory | Authorized laboratory professional verifies released result, method, status, and corrections |
-| Statistics | Qualified statistician verifies analysis set, estimand, method, denominator, missingness, and output |
-| Safety | Qualified safety professional verifies coding, seriousness, severity, causality, expectedness, and reportability |
-| Privacy/legal | Authorized reviewer verifies data use, consent/authorization, disclosure, de-identification method, and jurisdiction |
-| Regulatory | Qualified professional verifies adopted guidance, regional requirements, format, and submission process |
-| Publication | All accountable authors verify content and current journal instructions |
-
-## Review record
-
-Record:
-
-- reviewer role, not a fabricated name;
-- scope reviewed;
-- source version and data cut;
-- unresolved conflicts and limitations;
-- review date;
-- decision in the authorized workflow;
-- reference to the real sign-off record.
-
-Do not place a signature, license number, direct contact detail, or copied approval document in a synthetic asset.
-
-## Prohibited claims
-
-Never state that a script or checklist proves:
-
-- clinical correctness;
-- HIPAA compliance or de-identification;
-- GCP compliance;
-- CARE, CONSORT, SPIRIT, ICH, ACR, CAP, or CLIA compliance;
-- ethics approval or informed consent;
-- regulatory reportability;
-- readiness for signature, filing, publication, or submission.
-
-Permitted script language is limited to structural findings such as `BLOCKED`, `STRUCTURE_COMPLETE_REVIEW_REQUIRED`, or `PROCESS_DOCUMENTED_REVIEW_REQUIRED`.
-
-## Corrections and conflicts
-
-- Never overwrite a source fact.
-- Keep original and corrected versions linked.
-- Expose conflicting sources and stop dependent claims.
-- Require the responsible reviewer to resolve conflicts in the authorized system.
-- Re-run structural and consistency checks after any correction.
-
-No local script signs, timestamps an approval, files, transmits, or submits an artifact.

package/skills/clinical-reports/references/report_type_routing.md

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-# Report-Type Routing
-
-Select one route before opening a template. Do not merge routes merely because artifacts share clinical data.
-
-## Decision sequence
-
-1. Is the artifact a patient-care record?
-   Stop. This skill does not create SOAP notes, H&Ps, consultation notes, discharge summaries, prescriptions, orders, triage instructions, or signed diagnostic reports.
-2. Is it a single clinical case intended for publication?
-   Use CARE.
-3. Is it a diagnostic-report scaffold controlled by a clinical service?
-   Use ACR, the current specimen-specific CAP protocol, or CLIA as applicable.
-4. Is it a randomized-trial protocol?
-   Use SPIRIT 2025 and applicable extensions.
-5. Is it a randomized-trial results manuscript?
-   Use CONSORT 2025 and applicable extensions.
-6. Is it an integrated report of one clinical study for regulatory review?
-   Use ICH E3 plus E3 Q&A, with ICH E6(R3) and regional requirements as applicable.
-7. Is it individual pre-approval safety information?
-   Route to ICH E2A, E2B(R3), protocol/sponsor procedures, and regional requirements. Do not automate the reportability decision.
-8. Is it individual post-approval safety information?
-   Route to ICH E2D(R1), E2B(R3), marketing-authorisation-holder procedures, and regional requirements. Do not automate.
-9. Is it an aggregate safety table?
-   Use the protocol/SAP, ICH E3, CONSORT Harms when applicable, and the relevant regional aggregate-analysis guidance.
-10. Is it an aggregate research summary?
-    Use the reporting guideline for the actual design and the verified protocol/SAP. Do not imply clinical applicability.
-
-## Route matrix
-
-| Artifact | Base source | Add-ons | Do not substitute |
-|---|---|---|---|
-| Case report | CARE 2013 | CARE 2017 explanation; target journal | CONSORT, CSR, or diagnostic-report rules |
-| Radiology scaffold | ACR 2025 communication parameter | Current modality/program standard and local policy | A generic impression generator |
-| Cancer pathology scaffold | Current CAP protocol for exact organ/specimen | Current biomarker protocol and local policy | A static generic TNM checklist |
-| Laboratory scaffold | 42 CFR 493.1291 for applicable US nonwaived testing | Method, specialty, state, accreditor, and laboratory policy | Hardcoded reference or critical ranges |
-| Trial protocol | SPIRIT 2025 | Current design/data/intervention extensions | CONSORT results checklist |
-| Randomized results | CONSORT 2025 | Current design/data/intervention extensions; CONSORT Harms | SPIRIT protocol checklist |
-| CSR | ICH E3 and E3 Q&A | E6(R3), protocol, SAP, regional submission rules | CONSORT alone |
-| Pre-approval ICSR | ICH E2A and E2B(R3) | Regional law/guidance and sponsor procedure | Aggregate formatter |
-| Post-approval ICSR | ICH E2D(R1) and E2B(R3) | Regional law/guidance and MAH procedure | Pre-approval timing rules |
-| Periodic aggregate safety | ICH E2C(R2), where applicable | Regional periodic-report rules | E2B message schema |
-
-## CONSORT/SPIRIT extension selection
-
-The base statements address standard randomized trials. Check the live official extension catalogue for:
-
-- design: adaptive, cluster, cluster-crossover, crossover, dose-finding, factorial, multi-arm, non-inferiority/equivalence, N-of-1, pilot/feasibility, pragmatic, stepped-wedge, routine-data, or within-person;
-- data: abstracts, harms, outcomes, patient-reported outcomes, surrogate outcomes, equity, and pathology;
-- intervention/population: non-pharmacological, AI, social/psychological, children/adolescents, or other specialty extensions.
-
-Some current extensions were developed against CONSORT 2010 or SPIRIT 2013. Use the current extension with the 2025 base statement, document any conflict, and have a qualified methodologist resolve it. Do not silently renumber or reinterpret extension items.
-
-## Jurisdiction and role gate
-
-ICH Step 4 adoption does not itself prove implementation in a jurisdiction. FDA guidance is generally nonbinding but regulations are legally operative within scope. Institutional policy, protocol, contracts, ethics determinations, and sponsor procedures may add or change duties.
-
-Record the jurisdiction, regulated-product category, responsible role, source version/date, and reviewer before drafting. If any is unknown, mark the route `BLOCKED_UNRESOLVED`.

package/skills/clinical-reports/references/safety_reporting.md

@@ -1,109 +0,0 @@
-# Safety Reporting Boundaries
-
-Safety reporting is role-, product-, phase-, source-, jurisdiction-, and time-dependent. This skill formats verified aggregate counts only. It does not determine seriousness, severity, causality, expectedness, reportability, clock start, destination, format, or follow-up.
-
-## Core distinctions
-
-- **Adverse event (AE)**: an untoward medical occurrence temporally associated with a medicinal product; causality is not required.
-- **Adverse reaction / suspected adverse reaction**: a causal relationship is at least reasonably possible or otherwise meets the applicable regional definition.
-- **Seriousness**: outcome or regulatory criterion such as death, life-threatening experience at the time, hospitalization, disability/incapacity, congenital anomaly, or another medically important event.
-- **Severity**: intensity. A severe event is not automatically serious; a serious event need not be severe in intensity.
-- **Expectedness**: comparison with the applicable reference safety information under the governing procedure.
-
-Only an authorized qualified safety professional may make or approve these assessments.
-
-## ICH routes
-
-### E2A — pre-approval expedited reporting
-
-ICH E2A (Step 4, 27 October 1994) defines standards for expedited reporting during clinical development. It describes minimum information for an initial report and the distinction among serious, unexpected, and suspected reactions.
-
-Do not apply E2A as a universal post-approval rule or encode its timelines without the current regional requirement and sponsor procedure.
-
-### E2B(R3) — ICSR electronic data and message specification
-
-E2B(R3) defines data elements and electronic transmission for individual case safety reports. It covers pre- and post-approval ICSRs within scope. It does not:
-
-- decide whether a case is reportable;
-- define an aggregate safety table;
-- replace E2A, E2D(R1), or regional rules;
-- validate clinical coding or narrative accuracy.
-
-The ICH index listed E2B(R3) Q&As at Step 5 dated 18 July 2025 when checked. Use the current implementation guide, Q&As, code lists, regional implementation guide, and receiving-system rules.
-
-### E2D(R1) — post-approval individual cases
-
-ICH adopted E2D(R1), **Post-Approval Safety Data: Definitions and Standards for Management and Reporting of Individual Case Safety Reports**, on 15 September 2025.
-
-It addresses post-approval ICSR sources and case management, including organized data collection systems, literature, digital platforms, and patient-support programs. It explicitly directs users to:
-
-- E2B for ICSR structure/format/data elements;
-- E2C for periodic aggregate safety reporting;
-- regional/local requirements where they differ.
-
-Do not use the aggregate formatter for an ICSR or use E2D(R1) to invent missing case data.
-
-### E2C(R2) — periodic aggregate reporting
-
-Where applicable, E2C(R2) addresses periodic benefit-risk evaluation reporting. Applicability and regional format require qualified review. Aggregate tables in this skill are display aids, not periodic reports.
-
-## FDA IND safety reporting
-
-For applicable US IND studies, 21 CFR 312.32 controls sponsor IND safety reporting. FDA issued final sponsor and investigator safety-reporting guidances in December 2025. The sponsor guidance includes aggregate-data assessment considerations; the investigator guidance clarifies investigator-to-sponsor and IRB responsibilities.
-
-FDA’s IND safety-reporting page, current 23 June 2026 when checked, states:
-
-- sponsors report qualifying potential serious risks under 21 CFR 312.32;
-- unexpected fatal or life-threatening suspected adverse reactions have a 7-calendar-day outer limit after the relevant sponsor determination/receipt described by the regulation;
-- other qualifying reports generally use the applicable 15-calendar-day requirement;
-- as of 1 April 2026, commercial IND reports under 21 CFR 312.32(c)(1)(i) use FDA AEMS with E2B(R3), with stated exemptions for noncommercial INDs;
-- other categories described on the page use the applicable eCTD route.
-
-This summary is not a reporting clock or filing instruction. The responsible sponsor, investigator, IRB/IEC, and regulatory professionals must consult the current regulation, guidance, protocol, and procedures for each event.
-
-## Aggregate formatter input
-
-`format_adverse_events.py` accepts only aggregate rows:
-
-- analysis set;
-- treatment group;
-- MedDRA version;
-- system organ class;
-- preferred term;
-- subjects affected;
-- event count;
-- denominator.
-
-It also requires a populated `clinical_trial_safety_aggregate_template.json` sidecar
-that records authorization, protocol/SAP/data-cut references, analysis set, counting
-and threshold rules, MedDRA version/language, provenance, and pending human reviews.
-
-It rejects row-level identifiers, verbatim narratives, case IDs, and onset dates. It checks arithmetic and group consistency but does not verify:
-
-- MedDRA term/code validity;
-- coding quality or hierarchy placement;
-- treatment relatedness;
-- seriousness or fatality;
-- analysis-set correctness;
-- deduplication;
-- whether a subject appears in multiple terms or SOCs;
-- statistical inference.
-
-## MedDRA caveats
-
-MedDRA 29.0 (March 2026; transition date 4 May 2026) was current when this skill was refreshed. A report must use the study/sponsor-authorized dictionary version, not automatically the newest version.
-
-State the exact version and language. Terms can change currency, names, or hierarchy across releases; codes can persist through renames. Use licensed official files and MedDRA Points to Consider. A syntax checker cannot validate coding.
-
-## Required handoff
-
-Every aggregate table must disclose:
-
-- analysis set and denominator per group;
-- whether values are subjects, events, or both;
-- MedDRA version and language;
-- counting rules and threshold supplied by the protocol/SAP;
-- missing or suppressed cells;
-- no inferential claim unless separately verified;
-- qualified safety and statistical review required;
-- not suitable for individual-case submission.