Pharmacovigilance Safety Analyzer

Systematic drug safety analysis using FAERS adverse event data, FDA labeling, PharmGKB pharmacogenomics, and clinical trial safety signals.

KEY PRINCIPLES:

1. Report-first approach - Create report file FIRST, update progressively
2. Signal quantification - Use disproportionality measures (PRR, ROR)
3. Severity stratification - Prioritize serious/fatal events
4. Multi-source triangulation - FAERS, labels, trials, literature
5. Pharmacogenomic context - Include genetic risk factors
6. Actionable output - Risk-benefit summary with recommendations
7. English-first queries - Always use English drug names in tool calls

When to Use

Apply when user asks:

• "What are the safety concerns for [drug]?"
• "What adverse events are associated with [drug]?"
• "Is [drug] safe? What are the risks?"
• "Compare safety profiles of [drug A] vs [drug B]"
• "Pharmacovigilance analysis for [drug]"

Critical Workflow Requirements

Report-First Approach (MANDATORY)

1. Create [DRUG]_safety_report.md FIRST with all section headers and [Researching...] placeholders
2. Progressively update as data is gathered
3. Output separate data files: [DRUG]_adverse_events.csv and [DRUG]_pharmacogenomics.csv

Citation Requirements (MANDATORY)

Every safety signal MUST include source tool, data period, PRR, case counts, and serious/fatal breakdown.

Tool Parameter Reference (CRITICAL)

Workflow Overview

Phase 1: Drug Disambiguation
  -> Resolve drug name, get identifiers (ChEMBL, DrugBank)

Phase 2: Adverse Event Profiling (FAERS)
  -> Query FAERS, calculate PRR, stratify by seriousness

Phase 3: Label Warning Extraction
  -> DailyMed boxed warnings, contraindications, precautions

Phase 4: Pharmacogenomic Risk
  -> PharmGKB clinical annotations, high-risk genotypes

Phase 5: Clinical Trial Safety
  -> ClinicalTrials.gov Phase 3/4 safety data

Phase 5.5: Pathway & Mechanism Context
  -> KEGG drug metabolism, target pathway analysis

Phase 5.6: Literature Intelligence
  -> PubMed, BioRxiv/MedRxiv, OpenAlex citation analysis

Phase 6: Signal Prioritization
  -> Rank by PRR x severity x frequency

Phase 7: Report Synthesis

Phase 1: Drug Disambiguation

1. Search DailyMed via DailyMed_search_spls(drug_name=...) for NDC, SPL setid, generic name
2. Search ChEMBL via ChEMBL_search_drugs(query=...) for molecule ID, max phase
3. Document: generic name, brand names, drug class, mechanism, approval date

Phase 2: Adverse Event Profiling (FAERS)

1. Query FAERS_count_reactions_by_drug_event(drug_name=..., limit=50) for top events
2. For each event, get detailed breakdown (serious, fatal, hospitalization counts)
3. Calculate PRR: (A/B) / (C/D) where A=drug+event, B=drug+any, C=event+any_other, D=total_other
4. Apply signal thresholds: PRR > 2.0 (signal), > 3.0 (strong signal), case count >= 3

Severity classification:

• Fatal (highest priority), Life-threatening, Hospitalization, Disability, Other serious, Non-serious

See SIGNAL_DETECTION.md for detailed disproportionality formulas and example output tables.

Phase 3: Label Warning Extraction

1. Get label via DailyMed_get_spl_by_set_id(setid=...)
2. Extract: boxed warnings, contraindications, warnings/precautions, drug interactions
3. Categorize severity: Boxed Warning > Contraindication > Warning > Precaution

Phase 4: Pharmacogenomic Risk

1. Search PharmGKB_search_drug(query=...) for clinical annotations
2. Document actionable variants with evidence levels (1A/1B/2A/2B/3)
3. Note CPIC/DPWG guideline status

PGx Evidence Levels:

Phase 5: Clinical Trial Safety

1. Search search_clinical_trials(intervention=..., phase="Phase 3", status="Completed")
2. Extract serious AE rates, discontinuation rates, deaths
3. Compare drug vs placebo rates

Phase 5.5: Pathway & Mechanism Context

1. Query KEGG for drug metabolism pathways
2. Analyze target pathways for mechanistic basis of AEs
3. Document pathway-AE relationships

Phase 5.6: Literature Intelligence

1. PubMed: PubMed_search_articles(query='"[drug]" AND (safety OR adverse OR toxicity)')
2. BioRxiv/MedRxiv: Search for recent preprints (flag as not peer-reviewed)
3. OpenAlex: Citation analysis for key safety papers

Phase 6: Signal Prioritization

Signal Score = PRR x Severity_Weight x log10(Case_Count + 1)

Severity weights: Fatal=10, Life-threatening=8, Hospitalization=5, Disability=5, Other serious=3, Non-serious=1

Categorize signals:

• Critical (immediate attention): High PRR + fatal outcomes
• Moderate (monitor): Moderate PRR + serious outcomes
• Known/Expected (manage clinically): Low PRR, in label

Output Report

Save as [DRUG]_safety_report.md. See REPORT_TEMPLATES.md for the full report structure and example outputs.

Evidence Grading

Fallback Chains

Completeness Checklist

See CHECKLIST.md for the full phase-by-phase verification checklist.

References

• FAERS: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers
• DailyMed: https://dailymed.nlm.nih.gov
• PharmGKB: https://www.pharmgkb.org
• ClinicalTrials.gov: https://clinicaltrials.gov
• OpenFDA: https://open.fda.gov
• KEGG Drug: https://www.genome.jp/kegg/drug
• Tool documentation: TOOLS_REFERENCE.md