tooluniverse-pharmacovigilance - Claude MCP Skill

# 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

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## 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]"

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## 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.

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## Tool Parameter Reference (CRITICAL)

| Tool | WRONG Parameter | CORRECT Parameter |
|------|-----------------|-------------------|
| `FAERS_count_reactions_by_drug_event` | `drug` | `drug_name` |
| `DailyMed_search_spls` | `name` | `drug_name` |
| `PharmGKB_search_drug` | `drug` | `query` |
| `OpenFDA_get_drug_events` | `drug_name` | `search` |

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## 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](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**:
| Level | Description | Action |
|-------|-------------|--------|
| 1A | CPIC/DPWG guideline, implementable | Follow guideline |
| 1B | CPIC/DPWG guideline, annotation | Consider testing |
| 2A | VIP annotation, moderate evidence | May inform |
| 2B | VIP annotation, weaker evidence | Research |
| 3 | Low-level annotation | Not actionable |

## 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

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## Output Report

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

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## Evidence Grading

| Tier | Criteria | Example |
|------|----------|---------|
| T1 | PRR >10, fatal outcomes, boxed warning | Lactic acidosis |
| T2 | PRR 3-10, serious outcomes | Hepatotoxicity |
| T3 | PRR 2-3, moderate concern | Hypoglycemia |
| T4 | PRR <2, known/expected | GI side effects |

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## Fallback Chains

| Primary Tool | Fallback 1 | Fallback 2 |
|--------------|------------|------------|
| `FAERS_count_reactions_by_drug_event` | `OpenFDA_get_drug_events` | Literature search |
| `DailyMed_get_spl_by_set_id` | `FDA_drug_label_search` | DailyMed website |
| `PharmGKB_search_drug` | `CPIC_get_guidelines` | Literature search |
| `search_clinical_trials` | `ClinicalTrials.gov` API | PubMed for trial results |

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## Completeness Checklist

See [CHECKLIST.md](CHECKLIST.md) for the full phase-by-phase verification checklist.

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## 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](TOOLS_REFERENCE.md)