@bgicli/bgicli 2.1.1 → 2.2.0

package/data/skills/tooluniverse-clinical-trial-matching/SKILL.md

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+---
+name: tooluniverse-clinical-trial-matching
+description: AI-driven patient-to-trial matching for precision medicine and oncology. Given a patient profile (disease, molecular alterations, stage, prior treatments), discovers and ranks clinical trials from ClinicalTrials.gov using multi-dimensional matching across molecular eligibility, clinical criteria, drug-biomarker alignment, evidence strength, and geographic feasibility. Produces a quantitative Trial Match Score (0-100) per trial with tiered recommendations and a comprehensive markdown report. Use when oncologists, molecular tumor boards, or patients ask about clinical trial options for specific cancer types, biomarker profiles, or post-progression scenarios.
+---
+
+# Clinical Trial Matching for Precision Medicine
+
+Transform patient molecular profiles and clinical characteristics into prioritized clinical trial recommendations. Searches ClinicalTrials.gov and cross-references with molecular databases (CIViC, OpenTargets, ChEMBL, FDA) to produce evidence-graded, scored trial matches.
+
+**KEY PRINCIPLES**:
+1. **Report-first approach** - Create report file FIRST, then populate progressively
+2. **Patient-centric** - Every recommendation considers the individual patient's profile
+3. **Molecular-first matching** - Prioritize trials targeting patient's specific biomarkers
+4. **Evidence-graded** - Every recommendation has an evidence tier (T1-T4)
+5. **Quantitative scoring** - Trial Match Score (0-100) for every trial
+6. **Eligibility-aware** - Parse and evaluate inclusion/exclusion criteria
+7. **Actionable output** - Clear next steps, contact info, enrollment status
+8. **Source-referenced** - Every statement cites the tool/database source
+9. **Completeness checklist** - Mandatory section showing analysis coverage
+10. **English-first queries** - Always use English terms in tool calls. Respond in user's language
+
+---
+
+## When to Use
+
+Apply when user asks:
+- "What clinical trials are available for my NSCLC with EGFR L858R?"
+- "Patient has BRAF V600E melanoma, failed ipilimumab - what trials?"
+- "Find basket trials for NTRK fusion"
+- "Breast cancer with HER2 amplification, post-CDK4/6 inhibitor trials"
+- "KRAS G12C colorectal cancer clinical trials"
+- "Immunotherapy trials for TMB-high solid tumors"
+- "Clinical trials near Boston for lung cancer"
+- "What are my options after failing osimertinib for EGFR+ NSCLC?"
+
+**NOT for** (use other skills instead):
+- Single variant interpretation without trial focus -> Use `tooluniverse-cancer-variant-interpretation`
+- Drug safety profiling -> Use `tooluniverse-adverse-event-detection`
+- Target validation -> Use `tooluniverse-drug-target-validation`
+- General disease research -> Use `tooluniverse-disease-research`
+
+---
+
+## Input Parsing
+
+### Required Input
+- **Disease/cancer type**: Free-text disease name (e.g., "non-small cell lung cancer", "melanoma")
+
+### Strongly Recommended
+- **Molecular alterations**: One or more biomarkers (e.g., "EGFR L858R", "KRAS G12C", "PD-L1 50%", "TMB-high")
+- **Stage/grade**: Disease stage (e.g., "Stage IV", "metastatic", "locally advanced")
+- **Prior treatments**: Previous therapies and outcomes (e.g., "failed platinum chemotherapy", "progressed on osimertinib")
+
+### Optional
+- **Performance status**: ECOG or Karnofsky score (e.g., "ECOG 0-1")
+- **Geographic location**: City/state for proximity filtering (e.g., "Boston, MA")
+- **Trial phase preference**: I, II, III, IV, or "any"
+- **Intervention type**: drug, biological, device, etc.
+- **Recruiting status preference**: recruiting, not yet recruiting, active
+
+### Biomarker Parsing Rules
+
+| Input Format | Parsed As | Example |
+|-------------|-----------|---------|
+| Gene + amino acid change | Specific mutation | EGFR L858R |
+| Gene + exon notation | Exon-level alteration | EGFR exon 19 deletion |
+| Gene + fusion partner | Fusion | EML4-ALK fusion |
+| Gene + amplification | Copy number gain | HER2 amplification |
+| Gene + expression level | Expression biomarker | PD-L1 50% |
+| Gene + status | Status biomarker | MSI-high, TMB-high |
+| Gene + resistance | Resistance mutation | EGFR T790M |
+
+### Gene Symbol Normalization
+
+| Common Alias | Official Symbol | Notes |
+|-------------|----------------|-------|
+| HER2 | ERBB2 | Search both in trials |
+| PD-L1 | CD274 | Often searched as "PD-L1" in trials |
+| ALK | ALK | EML4-ALK is a fusion |
+| VEGF | VEGFA | Often searched as "VEGF" |
+| PD-1 | PDCD1 | Search as "PD-1" in trials |
+| BRCA | BRCA1/BRCA2 | Specify which BRCA gene |
+
+---
+
+## Phase 0: Tool Parameter Reference (CRITICAL)
+
+**BEFORE calling ANY tool**, verify its parameters from this reference table.
+
+### Clinical Trial Tools
+
+| Tool | Parameters | Notes |
+|------|-----------|-------|
+| `search_clinical_trials` | `query_term` (REQUIRED str), `condition` (str), `intervention` (str), `pageSize` (int, default 10), `pageToken` (str) | Main search. Returns `{studies: [{NCT ID, brief_title, brief_summary, overall_status, condition, phase}], nextPageToken, total_count}` |
+| `clinical_trials_search` | `action` (REQUIRED, must be `"search_studies"`), `condition` (str), `intervention` (str), `limit` (int) | Alternative search. Returns `{total_count, studies: [{nctId, title, status, conditions}]}` |
+| `clinical_trials_get_details` | `action` (REQUIRED, must be `"get_study_details"`), `nct_id` (REQUIRED str) | Full trial details. Returns `{nctId, title, summary, eligibility: {eligibilityCriteria}, ...}` |
+| `get_clinical_trial_eligibility_criteria` | `nct_ids` (REQUIRED array), `eligibility_criteria` (REQUIRED str, use `"all"`) | Returns `[{NCT ID, eligibility_criteria}]` |
+| `get_clinical_trial_locations` | `nct_ids` (REQUIRED array), `location` (REQUIRED str, use `"all"`) | Returns `[{NCT ID, locations: [{facility, city, state, country}]}]` |
+| `get_clinical_trial_descriptions` | `nct_ids` (REQUIRED array), `description_type` (REQUIRED str: `"brief"` or `"full"`) | Returns `[{NCT ID, brief_title, official_title, brief_summary, detailed_description}]` |
+| `get_clinical_trial_status_and_dates` | `nct_ids` (REQUIRED array), `status_and_date` (REQUIRED str, use `"all"`) | Returns `[{NCT ID, overall_status, start_date, primary_completion_date, completion_date}]` |
+| `get_clinical_trial_conditions_and_interventions` | `nct_ids` (REQUIRED array), `condition_and_intervention` (REQUIRED str, use `"all"`) | Returns `[{NCT ID, condition, arm_groups, interventions}]` |
+| `get_clinical_trial_outcome_measures` | `nct_ids` (REQUIRED array), `outcome_measures` (str: `"primary"`, `"secondary"`, `"all"`) | Returns `[{NCT ID, primary_outcomes, secondary_outcomes}]` |
+| `extract_clinical_trial_outcomes` | `nct_ids` (REQUIRED array), `outcome_measure` (str) | Returns trial outcome results |
+| `extract_clinical_trial_adverse_events` | `nct_ids` (REQUIRED array), `adverse_event_type` (str) | Returns adverse event data |
+
+### Molecular/Disease Tools
+
+| Tool | Parameters | Notes |
+|------|-----------|-------|
+| `MyGene_query_genes` | `query` (str), `species` (str) | Returns `{hits: [{symbol, entrezgene, ensembl: {gene}, name}]}` |
+| `OpenTargets_get_target_id_description_by_name` | `targetName` (str) | Returns `{data: {search: {hits: [{id, name, description}]}}}` |
+| `OpenTargets_get_disease_id_description_by_name` | `diseaseName` (str) | Returns `{data: {search: {hits: [{id, name, description}]}}}` |
+| `OpenTargets_get_associated_drugs_by_target_ensemblID` | `ensemblId` (str), `size` (int) | Returns `{data: {target: {knownDrugs: {count, rows: [{drug: {id, name, isApproved}, phase, mechanismOfAction, disease: {id, name}}]}}}}` |
+| `OpenTargets_get_associated_drugs_by_disease_efoId` | `efoId` (str), `size` (int) | Returns `{data: {disease: {knownDrugs: {count, rows: [...]}}}}` |
+| `OpenTargets_get_drug_id_description_by_name` | `drugName` (str) | Returns `{data: {search: {hits: [{id, name, description}]}}}` |
+| `OpenTargets_get_drug_mechanisms_of_action_by_chemblId` | `chemblId` (str) | Returns `{data: {drug: {mechanismsOfAction: {rows: [{mechanismOfAction, actionType, targetName, targets}]}}}}` |
+| `OpenTargets_get_approved_indications_by_drug_chemblId` | `chemblId` (str) | Returns `{data: {drug: {approvedIndications: [efoIds]}}}` |
+| `OpenTargets_target_disease_evidence` | `ensemblId` (str), `efoId` (str), `size` (int) | Returns target-disease evidence rows |
+
+### CIViC Tools
+
+| Tool | Parameters | Notes |
+|------|-----------|-------|
+| `civic_search_variants` | `query` (str), `limit` (int) | Does NOT filter by query. Returns alphabetically sorted variants |
+| `civic_get_variants_by_gene` | `gene_id` (int, CIViC gene ID), `limit` (int) | Returns `{data: {gene: {variants: {nodes: [{id, name}]}}}}`. Max 100 per call |
+| `civic_search_evidence_items` | `query` (str), `limit` (int) | Does NOT filter by query. Returns evidence alphabetically |
+| `civic_get_variant` | `variant_id` (int) | Returns `{data: {variant: {id, name}}}` |
+| `civic_search_therapies` | `query` (str), `limit` (int) | Search therapies |
+| `civic_search_diseases` | `query` (str), `limit` (int) | Search diseases |
+
+**Known CIViC Gene IDs**: EGFR=19, BRAF=5, ALK=1, ABL1=4, KRAS=30, TP53=45, ERBB2=20, NTRK1=197, NTRK2=560, NTRK3=561, PIK3CA=37, MET=52, ROS1=118, RET=122, BRCA1=2370, BRCA2=2371
+
+### Drug Information Tools
+
+| Tool | Parameters | Notes |
+|------|-----------|-------|
+| `drugbank_get_targets_by_drug_name_or_drugbank_id` | `query`, `case_sensitive`, `exact_match`, `limit` (ALL REQUIRED) | Returns `{results: [{drug_name, drugbank_id, targets: [{name, organism, actions}]}]}` |
+| `drugbank_get_indications_by_drug_name_or_drugbank_id` | `query`, `case_sensitive`, `exact_match`, `limit` (ALL REQUIRED) | Returns drug indications |
+| `ChEMBL_search_drugs` | `query` (str), `limit` (int) | Returns `{status, data: {drugs: [...]}}` |
+| `ChEMBL_get_drug_mechanisms` | `drug_chembl_id__exact` (str) | Returns drug mechanisms |
+| `fda_pharmacogenomic_biomarkers` | `drug_name` (opt str), `biomarker` (opt str), `limit` (opt int, default 10) | Returns `{count, shown, results: [{Drug, TherapeuticArea, Biomarker, LabelingSection}]}`. Use `limit=1000` to get all. |
+| `FDA_get_indications_by_drug_name` | `drug_name` (str), `limit` (int) | Returns FDA indications text |
+| `FDA_get_mechanism_of_action_by_drug_name` | `drug_name` (str), `limit` (int) | Returns FDA MoA text |
+| `FDA_get_clinical_studies_info_by_drug_name` | `drug_name` (str), `limit` (int) | Returns FDA clinical study info |
+| `FDA_get_adverse_reactions_by_drug_name` | `drug_name` (str), `limit` (int) | Returns adverse reactions |
+
+### Disease Ontology Tools
+
+| Tool | Parameters | Notes |
+|------|-----------|-------|
+| `ols_search_efo_terms` | `query` (str), `limit` (int) | Returns `{data: {terms: [{iri, obo_id, short_form, label, description}]}}` |
+| `ols_get_efo_term` | `term_id` (str) | Get specific EFO term details |
+| `ols_get_efo_term_children` | `term_id` (str) | Get child terms |
+
+### Literature Tools
+
+| Tool | Parameters | Notes |
+|------|-----------|-------|
+| `PubMed_search_articles` | `query` (str), `max_results` (int) | Returns list of `{pmid, title, abstract, authors, journal, pub_date}` |
+| `openalex_literature_search` | `query` (str), `limit` (int) | Returns literature results |
+
+### PharmGKB Tools
+
+| Tool | Parameters | Notes |
+|------|-----------|-------|
+| `PharmGKB_search_genes` | `query` (str) | Returns gene pharmacogenomics data |
+| `PharmGKB_get_clinical_annotations` | `query` (str) | Returns clinical annotations |
+
+---
+
+## Workflow Overview
+
+```
+Input: Patient profile (disease + biomarkers + stage + prior treatments)
+
+Phase 1: Patient Profile Standardization
+  - Resolve disease to EFO/ontology IDs
+  - Parse molecular alterations to gene + variant
+  - Resolve gene symbols to Ensembl/Entrez IDs
+  - Classify biomarker actionability (FDA-approved vs investigational)
+
+Phase 2: Broad Trial Discovery
+  - Disease-based trial search (ClinicalTrials.gov)
+  - Biomarker-specific trial search
+  - Intervention-based search (for known drugs targeting patient's biomarkers)
+  - Collect NCT IDs for detailed analysis
+
+Phase 3: Trial Characterization
+  - Get eligibility criteria for top candidate trials
+  - Get conditions and interventions
+  - Get locations and status
+  - Get trial descriptions and phase information
+
+Phase 4: Molecular Eligibility Matching
+  - Parse eligibility criteria text for biomarker requirements
+  - Match patient's molecular profile to trial requirements
+  - Score molecular eligibility
+
+Phase 5: Drug-Biomarker Alignment
+  - Identify trial intervention drugs
+  - Check drug mechanisms against patient biomarkers (OpenTargets, ChEMBL)
+  - FDA approval status for biomarker-drug combinations
+  - Classify drugs (targeted therapy, immunotherapy, chemotherapy)
+
+Phase 6: Evidence Assessment
+  - FDA-approved biomarker-drug combinations
+  - Clinical trial results for similar patients (PubMed)
+  - CIViC clinical evidence
+  - PharmGKB pharmacogenomics
+  - Drug safety profiles
+
+Phase 7: Geographic & Feasibility Analysis
+  - Trial site locations
+  - Enrollment status and dates
+  - Distance from patient location (if provided)
+
+Phase 8: Alternative Options
+  - Basket trials (biomarker-driven, tumor-agnostic)
+  - Expanded access and compassionate use
+  - Related trials with different study designs
+
+Phase 9: Scoring & Ranking
+  - Calculate Trial Match Score (0-100) for each trial
+  - Tier classification (Optimal/Good/Possible/Exploratory)
+  - Rank by composite score
+  - Generate recommendations
+
+Phase 10: Report Synthesis
+  - Executive summary (top 3 trials)
+  - Patient profile summary
+  - Ranked trial list with detailed analysis
+  - Alternative options
+  - Evidence grading
+  - Completeness checklist
+```
+
+---
+
+## Phase 1: Patient Profile Standardization
+
+**Goal**: Resolve all patient inputs to standardized identifiers for cross-database queries.
+
+### 1.1 Disease Resolution
+
+```python
+def resolve_disease(tu, disease_name):
+    """Resolve disease name to EFO ID and standard terminology."""
+    # OpenTargets disease search
+    result = tu.tools.OpenTargets_get_disease_id_description_by_name(diseaseName=disease_name)
+    hits = result.get('data', {}).get('search', {}).get('hits', [])
+
+    if hits:
+        disease_info = hits[0]
+        return {
+            'efo_id': disease_info.get('id'),
+            'name': disease_info.get('name'),
+            'description': disease_info.get('description'),
+            'original_input': disease_name
+        }
+
+    # Fallback: OLS EFO search
+    ols_result = tu.tools.ols_search_efo_terms(query=disease_name, limit=5)
+    ols_terms = ols_result.get('data', {}).get('terms', [])
+    if ols_terms:
+        term = ols_terms[0]
+        return {
+            'efo_id': term.get('short_form'),
+            'name': term.get('label'),
+            'description': term.get('description', [''])[0] if term.get('description') else '',
+            'original_input': disease_name
+        }
+
+    return {'efo_id': None, 'name': disease_name, 'description': '', 'original_input': disease_name}
+```
+
+**Response**: `{efo_id: "EFO_0003060", name: "non-small cell lung carcinoma", description: "...", original_input: "..."}`
+
+### 1.2 Gene/Biomarker Resolution
+
+```python
+def resolve_gene(tu, gene_symbol):
+    """Resolve gene symbol to cross-database IDs."""
+    # Normalize common aliases
+    alias_map = {
+        'HER2': 'ERBB2', 'HER-2': 'ERBB2',
+        'PD-L1': 'CD274', 'PDL1': 'CD274',
+        'PD-1': 'PDCD1', 'PD1': 'PDCD1',
+        'VEGF': 'VEGFA',
+    }
+    normalized = alias_map.get(gene_symbol.upper(), gene_symbol)
+
+    # MyGene resolution
+    result = tu.tools.MyGene_query_genes(query=normalized, species='human')
+    hits = result.get('hits', [])
+
+    gene_hit = None
+    for hit in hits:
+        if hit.get('symbol', '').upper() == normalized.upper():
+            gene_hit = hit
+            break
+    if not gene_hit and hits:
+        gene_hit = hits[0]
+
+    if gene_hit:
+        ensembl = gene_hit.get('ensembl', {})
+        ensembl_id = ensembl.get('gene') if isinstance(ensembl, dict) else (ensembl[0].get('gene') if isinstance(ensembl, list) and ensembl else None)
+        return {
+            'symbol': gene_hit.get('symbol'),
+            'entrez_id': gene_hit.get('entrezgene'),
+            'ensembl_id': ensembl_id,
+            'name': gene_hit.get('name'),
+            'original_input': gene_symbol
+        }
+
+    return {'symbol': gene_symbol, 'entrez_id': None, 'ensembl_id': None, 'name': None, 'original_input': gene_symbol}
+```
+
+### 1.3 Biomarker Actionability Classification
+
+Classify each biomarker using FDA pharmacogenomic biomarkers list:
+
+```python
+def classify_biomarker_actionability(tu, gene_symbol, alteration):
+    """Classify biomarker as FDA-approved, guideline, or investigational."""
+    # Check FDA pharmacogenomic biomarkers
+    fda_result = tu.tools.fda_pharmacogenomic_biomarkers()
+    fda_biomarkers = fda_result.get('results', [])
+
+    fda_match = [b for b in fda_biomarkers if gene_symbol.upper() in str(b.get('Biomarker', '')).upper()]
+
+    if fda_match:
+        return {
+            'level': 'FDA-approved',
+            'drugs': [b.get('Drug') for b in fda_match],
+            'labeling_sections': [b.get('LabelingSection') for b in fda_match]
+        }
+
+    # Check OpenTargets for drugs targeting this gene
+    # (done in Phase 5)
+
+    return {'level': 'investigational', 'drugs': [], 'labeling_sections': []}
+```
+
+### 1.4 Parse Molecular Alterations
+
+```python
+def parse_biomarker(biomarker_text):
+    """Parse free-text biomarker into structured components."""
+    import re
+
+    # Pattern: "GENE VARIANT" (e.g., "EGFR L858R")
+    mutation_match = re.match(r'(\w+)\s+([A-Z]\d+[A-Z])', biomarker_text, re.IGNORECASE)
+    if mutation_match:
+        return {'gene': mutation_match.group(1), 'alteration': mutation_match.group(2), 'type': 'mutation'}
+
+    # Pattern: "GENE exon N deletion/insertion"
+    exon_match = re.match(r'(\w+)\s+exon\s+(\d+)\s+(\w+)', biomarker_text, re.IGNORECASE)
+    if exon_match:
+        return {'gene': exon_match.group(1), 'alteration': f'exon {exon_match.group(2)} {exon_match.group(3)}', 'type': 'exon_alteration'}
+
+    # Pattern: "GENE1-GENE2 fusion" or "GENE1/GENE2"
+    fusion_match = re.match(r'(\w+)[-/](\w+)\s*(fusion)?', biomarker_text, re.IGNORECASE)
+    if fusion_match:
+        return {'gene': fusion_match.group(2), 'alteration': f'{fusion_match.group(1)}-{fusion_match.group(2)}', 'type': 'fusion', 'partner': fusion_match.group(1)}
+
+    # Pattern: "GENE amplification"
+    amp_match = re.match(r'(\w+)\s+amplification', biomarker_text, re.IGNORECASE)
+    if amp_match:
+        return {'gene': amp_match.group(1), 'alteration': 'amplification', 'type': 'amplification'}
+
+    # Pattern: "PD-L1 XX%"
+    expression_match = re.match(r'([\w-]+)\s+(\d+%|high|low|positive|negative)', biomarker_text, re.IGNORECASE)
+    if expression_match:
+        return {'gene': expression_match.group(1), 'alteration': expression_match.group(2), 'type': 'expression'}
+
+    # Pattern: "MSI-high", "TMB-high"
+    status_match = re.match(r'(MSI|TMB|dMMR|MMR)[-\s]*(high|low|stable|deficient|proficient)', biomarker_text, re.IGNORECASE)
+    if status_match:
+        return {'gene': status_match.group(1), 'alteration': status_match.group(2), 'type': 'status'}
+
+    # Fallback: treat as gene name
+    return {'gene': biomarker_text.split()[0], 'alteration': ' '.join(biomarker_text.split()[1:]), 'type': 'unknown'}
+```
+
+---
+
+## Phase 2: Broad Trial Discovery
+
+**Goal**: Cast a wide net to find all potentially relevant clinical trials.
+
+### 2.1 Disease-Based Trial Search
+
+```python
+def search_trials_by_disease(tu, disease_name, status_filter=None, phase_filter=None, page_size=20):
+    """Search ClinicalTrials.gov by disease/condition."""
+    query_parts = []
+    if status_filter:
+        query_parts.append(f'AREA[OverallStatus]{status_filter}')
+    if phase_filter:
+        query_parts.append(phase_filter)
+
+    query_term = ' AND '.join(query_parts) if query_parts else disease_name
+
+    result = tu.tools.search_clinical_trials(
+        condition=disease_name,
+        query_term=query_term if query_parts else disease_name,
+        pageSize=page_size
+    )
+
+    # Response: {studies: [{NCT ID, brief_title, brief_summary, overall_status, condition, phase}], nextPageToken, total_count}
+    if isinstance(result, str):
+        return []  # No studies found
+
+    return result.get('studies', [])
+```
+
+### 2.2 Biomarker-Specific Trial Search
+
+```python
+def search_trials_by_biomarker(tu, gene_symbol, alteration, disease_name=None, page_size=15):
+    """Search trials mentioning specific biomarkers."""
+    # Search 1: Gene + alteration
+    biomarker_query = f'{gene_symbol} {alteration}' if alteration else gene_symbol
+
+    result = tu.tools.search_clinical_trials(
+        condition=disease_name if disease_name else '',
+        query_term=biomarker_query,
+        pageSize=page_size
+    )
+
+    if isinstance(result, str):
+        return []
+
+    return result.get('studies', [])
+```
+
+### 2.3 Intervention-Based Trial Search
+
+```python
+def search_trials_by_intervention(tu, drug_name, disease_name=None, page_size=10):
+    """Search trials by intervention/drug name."""
+    result = tu.tools.search_clinical_trials(
+        condition=disease_name if disease_name else '',
+        intervention=drug_name,
+        query_term=drug_name,
+        pageSize=page_size
+    )
+
+    if isinstance(result, str):
+        return []
+
+    return result.get('studies', [])
+```
+
+### 2.4 Alternative Search (clinical_trials_search)
+
+Use as a complement to the main search:
+
+```python
+def search_trials_alternative(tu, condition, intervention=None, limit=10):
+    """Alternative trial search with different API endpoint."""
+    params = {
+        'action': 'search_studies',
+        'condition': condition,
+        'limit': limit
+    }
+    if intervention:
+        params['intervention'] = intervention
+
+    result = tu.tools.clinical_trials_search(**params)
+
+    return result.get('studies', [])
+```
+
+### 2.5 Deduplication
+
+```python
+def deduplicate_trials(trial_lists):
+    """Merge and deduplicate trials from multiple searches."""
+    seen_ncts = set()
+    unique_trials = []
+
+    for trials in trial_lists:
+        for trial in trials:
+            nct = trial.get('NCT ID') or trial.get('nctId', '')
+            if nct and nct not in seen_ncts:
+                seen_ncts.add(nct)
+                unique_trials.append(trial)
+
+    return unique_trials
+```
+
+---
+
+## Phase 3: Trial Characterization
+
+**Goal**: Get detailed information for the top candidate trials.
+
+### 3.1 Get Eligibility Criteria (Batch)
+
+```python
+def get_trial_eligibility(tu, nct_ids):
+    """Get eligibility criteria for multiple trials."""
+    # Process in batches of 10
+    all_criteria = []
+    for i in range(0, len(nct_ids), 10):
+        batch = nct_ids[i:i+10]
+        result = tu.tools.get_clinical_trial_eligibility_criteria(
+            nct_ids=batch,
+            eligibility_criteria='all'
+        )
+        if isinstance(result, list):
+            all_criteria.extend(result)
+
+    return all_criteria
+    # Returns: [{NCT ID, eligibility_criteria: "Inclusion Criteria:\n...\nExclusion Criteria:\n..."}]
+```
+
+### 3.2 Get Conditions and Interventions (Batch)
+
+```python
+def get_trial_interventions(tu, nct_ids):
+    """Get conditions, arm groups, and interventions for multiple trials."""
+    all_interventions = []
+    for i in range(0, len(nct_ids), 10):
+        batch = nct_ids[i:i+10]
+        result = tu.tools.get_clinical_trial_conditions_and_interventions(
+            nct_ids=batch,
+            condition_and_intervention='all'
+        )
+        if isinstance(result, list):
+            all_interventions.extend(result)
+
+    return all_interventions
+    # Returns: [{NCT ID, condition, arm_groups: [{label, type, description, interventionNames}], interventions: [{type, name, description}]}]
+```
+
+### 3.3 Get Locations (Batch)
+
+```python
+def get_trial_locations(tu, nct_ids):
+    """Get trial site locations."""
+    all_locations = []
+    for i in range(0, len(nct_ids), 10):
+        batch = nct_ids[i:i+10]
+        result = tu.tools.get_clinical_trial_locations(
+            nct_ids=batch,
+            location='all'
+        )
+        if isinstance(result, list):
+            all_locations.extend(result)
+
+    return all_locations
+    # Returns: [{NCT ID, locations: [{facility, city, state, country}]}]
+```
+
+### 3.4 Get Status and Dates (Batch)
+
+```python
+def get_trial_status(tu, nct_ids):
+    """Get enrollment status and key dates."""
+    all_status = []
+    for i in range(0, len(nct_ids), 10):
+        batch = nct_ids[i:i+10]
+        result = tu.tools.get_clinical_trial_status_and_dates(
+            nct_ids=batch,
+            status_and_date='all'
+        )
+        if isinstance(result, list):
+            all_status.extend(result)
+
+    return all_status
+    # Returns: [{NCT ID, overall_status, start_date, primary_completion_date, completion_date}]
+```
+
+### 3.5 Get Full Descriptions (Batch)
+
+```python
+def get_trial_descriptions(tu, nct_ids):
+    """Get detailed trial descriptions."""
+    all_descriptions = []
+    for i in range(0, len(nct_ids), 10):
+        batch = nct_ids[i:i+10]
+        result = tu.tools.get_clinical_trial_descriptions(
+            nct_ids=batch,
+            description_type='full'
+        )
+        if isinstance(result, list):
+            all_descriptions.extend(result)
+
+    return all_descriptions
+    # Returns: [{NCT ID, brief_title, official_title, brief_summary, detailed_description}]
+```
+
+---
+
+## Phase 4: Molecular Eligibility Matching
+
+**Goal**: Determine how well the patient's molecular profile matches each trial's requirements.
+
+### 4.1 Parse Eligibility Text for Biomarker Requirements
+
+```python
+def extract_biomarker_requirements(eligibility_text):
+    """Extract biomarker requirements from eligibility criteria text."""
+    import re
+
+    requirements = {
+        'required_biomarkers': [],
+        'excluded_biomarkers': [],
+        'biomarker_agnostic': False
+    }
+
+    if not eligibility_text:
+        return requirements
+
+    text_upper = eligibility_text.upper()
+
+    # Common biomarker patterns in eligibility text
+    # Required biomarkers (in inclusion criteria)
+    inclusion_section = eligibility_text.split('Exclusion Criteria')[0] if 'Exclusion Criteria' in eligibility_text else eligibility_text
+    exclusion_section = eligibility_text.split('Exclusion Criteria')[1] if 'Exclusion Criteria' in eligibility_text else ''
+
+    # Look for gene mutation requirements
+    gene_patterns = [
+        r'(?:EGFR|KRAS|BRAF|ALK|ROS1|RET|MET|NTRK|HER2|ERBB2|PIK3CA|BRCA|PD-?L1|MSI|TMB|dMMR)',
+    ]
+
+    for pattern in gene_patterns:
+        # In inclusion section
+        for match in re.finditer(pattern, inclusion_section, re.IGNORECASE):
+            gene = match.group(0).upper()
+            context = inclusion_section[max(0, match.start()-100):match.end()+100]
+            requirements['required_biomarkers'].append({
+                'gene': gene,
+                'context': context.strip()
+            })
+
+        # In exclusion section
+        for match in re.finditer(pattern, exclusion_section, re.IGNORECASE):
+            gene = match.group(0).upper()
+            context = exclusion_section[max(0, match.start()-100):match.end()+100]
+            requirements['excluded_biomarkers'].append({
+                'gene': gene,
+                'context': context.strip()
+            })
+
+    # Check for biomarker-agnostic / basket trial language
+    basket_terms = ['tumor-agnostic', 'histology-independent', 'basket', 'any solid tumor', 'all comers', 'biomarker-selected']
+    if any(term in text_upper.lower() for term in basket_terms):
+        requirements['biomarker_agnostic'] = True
+
+    return requirements
+```
+
+### 4.2 Score Molecular Match
+
+```python
+def score_molecular_match(patient_biomarkers, trial_requirements):
+    """Score molecular match between patient and trial (0-40 points)."""
+    if not trial_requirements['required_biomarkers'] and not trial_requirements['excluded_biomarkers']:
+        # No molecular criteria - could be open to any
+        return 10, 'No specific molecular criteria (general trial)'
+
+    patient_genes = {b['gene'].upper() for b in patient_biomarkers}
+    required_genes = {b['gene'].upper() for b in trial_requirements['required_biomarkers']}
+    excluded_genes = {b['gene'].upper() for b in trial_requirements['excluded_biomarkers']}
+
+    # Check exclusions first
+    excluded_match = patient_genes & excluded_genes
+    if excluded_match:
+        return 0, f'Patient biomarker(s) {excluded_match} are in exclusion criteria'
+
+    if not required_genes:
+        return 10, 'No specific biomarker requirements found'
+
+    # Check for exact gene match
+    matched_genes = patient_genes & required_genes
+    if matched_genes:
+        # Check for specific variant match
+        # Look for specific mutation mentions in context
+        exact_variant_match = False
+        for req in trial_requirements['required_biomarkers']:
+            for pb in patient_biomarkers:
+                if pb['gene'].upper() == req['gene'].upper():
+                    alt = pb.get('alteration', '').upper()
+                    if alt and alt in req.get('context', '').upper():
+                        exact_variant_match = True
+                        break
+
+        if exact_variant_match:
+            return 40, f'Exact biomarker match: {matched_genes} with specific variant'
+        else:
+            return 30, f'Gene-level match: {matched_genes} (specific variant match unclear)'
+
+    # Check for pathway-level match (e.g., trial targets EGFR pathway, patient has EGFR mutation)
+    # This requires domain knowledge mapping
+    return 5, 'No direct biomarker match found'
+```
+
+---
+
+## Phase 5: Drug-Biomarker Alignment
+
+**Goal**: Verify that trial drugs actually target the patient's biomarkers.
+
+### 5.1 Identify Trial Drugs and Mechanisms
+
+```python
+def get_drug_mechanism_info(tu, drug_name):
+    """Get drug mechanism, targets, and approval status."""
+    # Step 1: Resolve drug in OpenTargets
+    result = tu.tools.OpenTargets_get_drug_id_description_by_name(drugName=drug_name)
+    hits = result.get('data', {}).get('search', {}).get('hits', [])
+
+    if not hits:
+        return {'drug_name': drug_name, 'chembl_id': None, 'mechanisms': [], 'is_approved': False}
+
+    drug_info = hits[0]
+    chembl_id = drug_info.get('id')
+
+    # Step 2: Get mechanisms of action
+    moa_result = tu.tools.OpenTargets_get_drug_mechanisms_of_action_by_chemblId(chemblId=chembl_id)
+    moa_rows = moa_result.get('data', {}).get('drug', {}).get('mechanismsOfAction', {}).get('rows', [])
+
+    mechanisms = []
+    for row in moa_rows:
+        targets = row.get('targets', [])
+        mechanisms.append({
+            'mechanism': row.get('mechanismOfAction'),
+            'action_type': row.get('actionType'),
+            'target_name': row.get('targetName'),
+            'target_genes': [t.get('approvedSymbol') for t in targets]
+        })
+
+    # Step 3: Check approval
+    approval_result = tu.tools.OpenTargets_get_drug_approval_status_by_chemblId(chemblId=chembl_id)
+
+    return {
+        'drug_name': drug_name,
+        'chembl_id': chembl_id,
+        'description': drug_info.get('description'),
+        'mechanisms': mechanisms,
+        'is_approved': 'approved' in drug_info.get('description', '').lower()
+    }
+```
+
+### 5.2 Score Drug-Biomarker Alignment
+
+```python
+def score_drug_biomarker_alignment(patient_gene_symbols, drug_mechanisms):
+    """Check if trial drug targets patient's biomarkers."""
+    patient_genes_upper = {g.upper() for g in patient_gene_symbols}
+
+    for mech in drug_mechanisms:
+        target_genes = {g.upper() for g in mech.get('target_genes', [])}
+        if patient_genes_upper & target_genes:
+            return True, f"Drug targets {patient_genes_upper & target_genes} via {mech.get('mechanism')}"
+
+    return False, "No direct target overlap with patient biomarkers"
+```
+
+---
+
+## Phase 6: Evidence Assessment
+
+**Goal**: Assess evidence strength for drug efficacy in similar patient populations.
+
+### 6.1 FDA Approval Evidence
+
+```python
+def check_fda_approval(tu, drug_name, disease_name):
+    """Check FDA approval status and labeled indications."""
+    result = tu.tools.FDA_get_indications_by_drug_name(drug_name=drug_name, limit=3)
+
+    indications = result.get('results', [])
+    for ind in indications:
+        ind_text = str(ind.get('indications_and_usage', ''))
+        # Check if disease is mentioned in indications
+        if any(term.lower() in ind_text.lower() for term in disease_name.split()):
+            return {
+                'approved': True,
+                'indication_text': ind_text[:500],
+                'brand_name': ind.get('openfda.brand_name', []),
+                'evidence_tier': 'T1'
+            }
+
+    return {'approved': False, 'indication_text': '', 'brand_name': [], 'evidence_tier': 'T3'}
+```
+
+### 6.2 Literature Evidence
+
+```python
+def get_literature_evidence(tu, gene, alteration, drug_name, disease_name):
+    """Search PubMed for evidence of drug efficacy for this biomarker."""
+    query = f'{gene} {alteration} {drug_name} {disease_name} clinical trial'
+    result = tu.tools.PubMed_search_articles(query=query, max_results=5)
+
+    articles = result if isinstance(result, list) else result.get('articles', [])
+    return articles
+```
+
+### 6.3 CIViC Evidence (if available)
+
+```python
+def get_civic_evidence(tu, gene_symbol, civic_gene_id):
+    """Get CIViC clinical evidence for gene variants."""
+    if not civic_gene_id:
+        return []
+
+    result = tu.tools.civic_get_variants_by_gene(gene_id=civic_gene_id, limit=100)
+    variants = result.get('data', {}).get('gene', {}).get('variants', {}).get('nodes', [])
+    return variants
+```
+
+### 6.4 Evidence Tier Classification
+
+| Tier | Symbol | Criteria | Score Impact |
+|------|--------|----------|-------------|
+| **T1** | [T1] | FDA-approved biomarker-drug, NCCN guideline | 20 points |
+| **T2** | [T2] | Phase III positive, clinical evidence | 15 points |
+| **T3** | [T3] | Phase I/II results, preclinical | 10 points |
+| **T4** | [T4] | Computational, mechanism inference | 5 points |
+
+---
+
+## Phase 7: Geographic & Feasibility Analysis
+
+**Goal**: Assess practical feasibility of trial enrollment.
+
+### 7.1 Location Analysis
+
+```python
+def analyze_trial_locations(locations_data, patient_location=None):
+    """Analyze trial site locations and proximity."""
+    if not locations_data:
+        return {'total_sites': 0, 'countries': [], 'us_states': [], 'nearest': None}
+
+    locations = locations_data.get('locations', [])
+    countries = list(set(loc.get('country', '') for loc in locations if loc.get('country')))
+    us_states = list(set(loc.get('state', '') for loc in locations if loc.get('country') == 'United States' and loc.get('state')))
+
+    return {
+        'total_sites': len(locations),
+        'countries': countries,
+        'us_states': us_states,
+        'has_us_sites': 'United States' in countries,
+        'locations': locations[:10]  # First 10 for display
+    }
+```
+
+### 7.2 Geographic Scoring
+
+| Criterion | Points |
+|-----------|--------|
+| Trial sites in patient's state/city | 5 |
+| Trial sites within 100 miles | 3 |
+| Trial sites in same country | 1 |
+| No location info or far away | 0 |
+
+---
+
+## Phase 8: Alternative Options
+
+**Goal**: Identify basket trials, expanded access, and related studies.
+
+### 8.1 Basket Trial Search
+
+**IMPORTANT**: ClinicalTrials.gov search is sensitive to query complexity. Overly specific queries like "NTRK fusion tumor agnostic" may return zero results. Use simpler queries and combine results.
+
+```python
+def search_basket_trials(tu, biomarker, page_size=10):
+    """Search for basket/biomarker-driven trials.
+
+    NOTE: Use simpler queries first (e.g., 'NTRK solid tumor'),
+    then more specific ones. Complex multi-word queries often fail.
+    """
+    # Start with simpler queries (more likely to return results)
+    query_terms = [
+        f'{biomarker} solid tumor',
+        f'{biomarker}',
+        f'{biomarker} basket',
+    ]
+
+    all_trials = []
+    for query in query_terms:
+        result = tu.tools.search_clinical_trials(
+            query_term=query,
+            pageSize=page_size
+        )
+        if not isinstance(result, str):
+            all_trials.extend(result.get('studies', []))
+
+    return deduplicate_trials([all_trials])
+```
+
+### 8.2 Expanded Access Search
+
+```python
+def search_expanded_access(tu, drug_name):
+    """Search for expanded access / compassionate use programs."""
+    result = tu.tools.search_clinical_trials(
+        query_term=f'{drug_name} expanded access',
+        pageSize=5
+    )
+
+    if isinstance(result, str):
+        return []
+
+    return result.get('studies', [])
+```
+
+---
+
+## Phase 9: Trial Match Scoring System
+
+### Score Components (Total: 0-100)
+
+**Molecular Match** (0-40 points):
+| Criterion | Points | Description |
+|-----------|--------|-------------|
+| Exact biomarker match | 40 | Trial requires patient's specific variant |
+| Gene-level match | 30 | Trial requires gene mutation, patient has specific variant |
+| Pathway match | 20 | Trial targets same pathway as patient's biomarker |
+| No molecular criteria | 10 | General disease trial |
+| Excluded biomarker | 0 | Patient's biomarker is in exclusion criteria |
+
+**Clinical Eligibility** (0-25 points):
+| Criterion | Points | Description |
+|-----------|--------|-------------|
+| All criteria met | 25 | Disease, stage, prior treatment all match |
+| Most criteria met | 18 | 1-2 criteria unclear |
+| Some criteria met | 10 | Several criteria unclear |
+| Clearly ineligible | 0 | Fails major criterion |
+
+**Evidence Strength** (0-20 points):
+| Criterion | Points | Description |
+|-----------|--------|-------------|
+| FDA-approved combination | 20 | T1 evidence |
+| Phase III positive | 15 | T2 evidence |
+| Phase II promising | 10 | T3 evidence |
+| Phase I or no results | 5 | T4 evidence |
+
+**Trial Phase** (0-10 points):
+| Phase | Points |
+|-------|--------|
+| Phase III | 10 |
+| Phase II | 8 |
+| Phase I/II | 6 |
+| Phase I | 4 |
+
+**Geographic Feasibility** (0-5 points):
+| Criterion | Points |
+|-----------|--------|
+| Patient's city/state | 5 |
+| Same country | 3 |
+| International only | 1 |
+| Unknown | 0 |
+
+### Recommendation Tiers
+
+| Score | Tier | Label | Action |
+|-------|------|-------|--------|
+| **80-100** | Tier 1 | Optimal Match | Strongly recommend - contact site immediately |
+| **60-79** | Tier 2 | Good Match | Recommend - discuss with care team |
+| **40-59** | Tier 3 | Possible Match | Consider - needs further eligibility review |
+| **0-39** | Tier 4 | Exploratory | Backup option - consider if Tier 1-3 unavailable |
+
+---
+
+## Phase 10: Report Synthesis
+
+### Report Template
+
+The final report should follow this structure:
+
+```markdown
+# Clinical Trial Matching Report
+
+**Patient**: [Disease type] with [biomarker(s)]
+**Date**: [Current date]
+**Trials Analyzed**: [N total] | **Top Matches**: [N with score >= 60]
+
+---
+
+## Executive Summary
+
+**Top 3 Trial Recommendations**:
+
+1. **[NCT ID]** - [Brief title] (Score: XX/100, Tier N)
+   - Phase: [Phase], Status: [Status]
+   - Why: [Key reason for match]
+
+2. **[NCT ID]** - [Brief title] (Score: XX/100, Tier N)
+   ...
+
+3. **[NCT ID]** - [Brief title] (Score: XX/100, Tier N)
+   ...
+
+---
+
+## Patient Profile Summary
+
+| Parameter | Value | Standardized |
+|-----------|-------|-------------|
+| Disease | [input] | [EFO name] (EFO_XXXX) |
+| Biomarker(s) | [input] | [gene: variant, type] |
+| Stage | [input] | [standardized] |
+| Prior Treatment | [input] | [standardized] |
+| Performance Status | [input] | [ECOG score] |
+| Location | [input] | [city, state] |
+
+### Biomarker Actionability
+| Biomarker | Actionability Level | FDA-Approved Drugs | Evidence |
+|-----------|--------------------|--------------------|----------|
+| [gene variant] | [FDA-approved/investigational] | [drugs] | [T1/T2/T3/T4] |
+
+---
+
+## Ranked Trial Matches
+
+### Trial 1: [NCT ID] - [Title]
+
+**Trial Match Score: XX/100** (Tier N: [Label])
+
+| Component | Score | Details |
+|-----------|-------|---------|
+| Molecular Match | XX/40 | [explanation] |
+| Clinical Eligibility | XX/25 | [explanation] |
+| Evidence Strength | XX/20 | [explanation] |
+| Trial Phase | XX/10 | [phase] |
+| Geographic | XX/5 | [location info] |
+
+**Trial Details**:
+- **Phase**: [Phase]
+- **Status**: [Recruiting/Active/etc.]
+- **Sponsor**: [Sponsor]
+- **Start Date**: [Date]
+- **Estimated Completion**: [Date]
+
+**Interventions**:
+- [Drug name]: [Mechanism] | [Dosing info if available]
+- [Comparator]: [Description]
+
+**Molecular Eligibility Match**:
+- Required biomarkers: [list]
+- Patient match: [Exact/Gene-level/Pathway/None]
+- Notes: [details]
+
+**Clinical Eligibility Assessment**:
+- Disease type: [Match/Mismatch]
+- Stage: [Match/Mismatch/Unclear]
+- Prior treatment: [Match/Mismatch/Unclear]
+- Performance status: [Match/Mismatch/Unclear]
+
+**Evidence for Efficacy**:
+- FDA approval: [Yes/No for this indication]
+- Clinical results: [Phase III/II/I data if available]
+- Mechanism alignment: [Drug targets patient's biomarker: Yes/No]
+- Literature: [Key references]
+
+**Trial Sites** (first 5):
+- [City, State, Country]
+- ...
+
+**Next Steps**: [Contact info, enrollment instructions]
+
+[Repeat for each matched trial]
+
+---
+
+## Trials by Category
+
+### Targeted Therapy Trials
+[List trials with targeted agents matching patient's biomarkers]
+
+### Immunotherapy Trials
+[List immunotherapy trials, noting PD-L1/TMB/MSI requirements]
+
+### Combination Therapy Trials
+[List trials with drug combinations]
+
+### Basket/Platform Trials
+[List biomarker-agnostic or multi-arm trials]
+
+---
+
+## Additional Testing Recommendations
+
+If the patient has not been tested for certain biomarkers, these trials would become relevant:
+
+| Biomarker | Test Needed | Trials Unlocked | Priority |
+|-----------|-------------|----------------|----------|
+| [e.g., TMB] | [NGS panel] | [NCT IDs] | [High/Medium/Low] |
+
+---
+
+## Alternative Options
+
+### Expanded Access Programs
+[List any expanded access or compassionate use programs]
+
+### Off-Label Options
+[FDA-approved drugs for other indications with same biomarker]
+
+---
+
+## Evidence Grading Summary
+
+| Evidence Tier | Count | Description |
+|--------------|-------|-------------|
+| T1 (FDA/Guideline) | N | FDA-approved biomarker-drug, clinical guideline |
+| T2 (Clinical) | N | Phase III data, robust clinical evidence |
+| T3 (Emerging) | N | Phase I/II, preclinical evidence |
+| T4 (Exploratory) | N | Computational, mechanism inference |
+
+---
+
+## Completeness Checklist
+
+| Analysis Step | Status | Source |
+|--------------|--------|--------|
+| Disease standardization | [Done/Partial/Failed] | [OpenTargets/OLS] |
+| Gene resolution | [Done/Partial/Failed] | [MyGene] |
+| Biomarker actionability | [Done/Partial/Failed] | [FDA biomarkers] |
+| Disease trial search | [Done/Partial/Failed] | [ClinicalTrials.gov] |
+| Biomarker trial search | [Done/Partial/Failed] | [ClinicalTrials.gov] |
+| Intervention trial search | [Done/Partial/Failed] | [ClinicalTrials.gov] |
+| Eligibility parsing | [Done/Partial/Failed] | [ClinicalTrials.gov] |
+| Drug mechanism analysis | [Done/Partial/Failed] | [OpenTargets/ChEMBL] |
+| Evidence assessment | [Done/Partial/Failed] | [FDA/PubMed/CIViC] |
+| Location analysis | [Done/Partial/Failed] | [ClinicalTrials.gov] |
+| Basket trial search | [Done/Partial/Failed] | [ClinicalTrials.gov] |
+| Expanded access search | [Done/Partial/Failed] | [ClinicalTrials.gov] |
+| Scoring & ranking | [Done/Partial/Failed] | [Composite] |
+
+---
+
+## Disclaimer
+
+This report is for informational and research purposes only. Clinical trial eligibility is ultimately determined by the trial investigators based on complete medical records. Patients should discuss all options with their healthcare team. Trial availability and status may change; verify current status at [ClinicalTrials.gov](https://clinicaltrials.gov).
+
+## Sources
+
+All data sourced from:
+- ClinicalTrials.gov (trial search, eligibility, locations, status)
+- OpenTargets Platform (drug-target associations, disease ontology)
+- CIViC (clinical variant interpretations)
+- ChEMBL (drug mechanisms, targets)
+- FDA (approved indications, pharmacogenomic biomarkers, drug labels)
+- DrugBank (drug targets, indications)
+- PharmGKB (pharmacogenomics)
+- PubMed/NCBI (literature evidence)
+- OLS/EFO (disease ontology)
+- MyGene (gene identifier resolution)
+```
+
+---
+
+## Execution Strategy
+
+### Parallelization Opportunities
+
+Many tool calls can be executed in parallel to speed up the workflow:
+
+**Parallel Group 1** (Phase 1 - can all run simultaneously):
+- `MyGene_query_genes` for each gene
+- `OpenTargets_get_disease_id_description_by_name` for disease
+- `ols_search_efo_terms` for disease
+- `fda_pharmacogenomic_biomarkers` (no params)
+
+**Parallel Group 2** (Phase 2 - can all run simultaneously):
+- `search_clinical_trials` with disease condition
+- `search_clinical_trials` with biomarker query
+- `search_clinical_trials` with intervention query
+- `clinical_trials_search` as alternative
+
+**Parallel Group 3** (Phase 3 - can all run simultaneously):
+- `get_clinical_trial_eligibility_criteria` for all NCT IDs
+- `get_clinical_trial_conditions_and_interventions` for all NCT IDs
+- `get_clinical_trial_locations` for all NCT IDs
+- `get_clinical_trial_status_and_dates` for all NCT IDs
+- `get_clinical_trial_descriptions` for all NCT IDs
+
+**Parallel Group 4** (Phases 5-6 - for each drug):
+- `OpenTargets_get_drug_id_description_by_name` for drug
+- `OpenTargets_get_drug_mechanisms_of_action_by_chemblId` for drug
+- `FDA_get_indications_by_drug_name` for drug
+- `PubMed_search_articles` for evidence
+
+### Error Handling
+
+For each tool call:
+1. Wrap in try/except
+2. Check for empty results
+3. Use fallback tools when primary fails
+4. Document what failed in completeness checklist
+5. Never let one failure block the entire analysis
+
+### Performance Optimization
+
+- Batch NCT IDs in groups of 10 for detail tools
+- Limit initial search to 20-30 trials per search strategy
+- Focus detailed analysis on top 15-20 candidates after initial filtering
+- Cache gene/disease resolution results for reuse across phases
+
+---
+
+## Common Use Patterns
+
+### Pattern 1: Targeted Therapy Matching (Most Common)
+
+**Input**: "NSCLC patient with EGFR L858R, failed platinum chemotherapy"
+
+1. Resolve: NSCLC -> EFO_0003060, EGFR -> ENSG00000146648
+2. Search: "non-small cell lung cancer" + "EGFR mutation" + "EGFR L858R"
+3. Filter: Recruiting trials with EGFR molecular requirements
+4. Match: Score trials by EGFR L858R specificity
+5. Drugs: Identify TKIs (osimertinib, erlotinib, etc.) in trial arms
+6. Evidence: Check FDA approval of EGFR TKIs for NSCLC
+7. Report: Prioritize targeted therapy trials, include immunotherapy options
+
+### Pattern 2: Immunotherapy Selection
+
+**Input**: "Melanoma, TMB-high, PD-L1 positive, failed ipilimumab"
+
+1. Resolve: Melanoma -> EFO_0000756
+2. Search: "melanoma" + "TMB" + "PD-L1" + "immunotherapy"
+3. Filter: Trials requiring PD-L1 or TMB testing
+4. Match: Score by TMB/PD-L1 requirements
+5. Drugs: Identify checkpoint inhibitors (pembrolizumab, nivolumab)
+6. Evidence: Check FDA approval for TMB-high indications
+7. Report: Focus on anti-PD-1/PD-L1 trials, combination immunotherapy
+
+### Pattern 3: Basket Trial Identification
+
+**Input**: "Any solid tumor with NTRK fusion"
+
+1. Resolve: NTRK genes (NTRK1, NTRK2, NTRK3)
+2. Search: "NTRK fusion" + "tumor agnostic" + "basket"
+3. Filter: Biomarker-agnostic trials
+4. Match: Score by NTRK-specific inclusion criteria
+5. Drugs: Identify larotrectinib, entrectinib
+6. Evidence: FDA tissue-agnostic approval for larotrectinib
+7. Report: Highlight tumor-agnostic approval, broad eligibility
+
+### Pattern 4: Post-Progression Options
+
+**Input**: "Breast cancer, failed CDK4/6 inhibitors, ESR1 mutation"
+
+1. Resolve: Breast cancer -> EFO_0000305, ESR1 -> ENSG00000091831
+2. Search: "breast cancer" + "ESR1" + "CDK4/6 resistance"
+3. Filter: Trials for post-CDK4/6 setting
+4. Match: Score by ESR1 mutation and prior treatment requirements
+5. Drugs: Identify novel endocrine agents, SERDs, ESR1-targeting drugs
+6. Evidence: Check clinical data for post-CDK4/6 options
+7. Report: Focus on resistance-overcoming strategies
+
+### Pattern 5: Geographic Search
+
+**Input**: "Lung cancer trials within 100 miles of Boston"
+
+1. Search: "lung cancer" (broad)
+2. Get locations for all candidate trials
+3. Filter: Sites in Massachusetts and nearby states
+4. Score: High geographic feasibility for Boston-area sites
+5. Report: Prioritize by proximity, include contact info
+
+---
+
+## Edge Case Handling
+
+### No Matching Trials Found
+
+If no trials match the patient's biomarker:
+1. Broaden search to gene-level (remove specific variant)
+2. Search for pathway-level trials
+3. Search basket trials
+4. Suggest additional biomarker testing
+5. Report alternative options (off-label, compassionate use)
+
+### Rare Biomarkers
+
+For uncommon mutations (e.g., unusual EGFR variants):
+1. Search gene-level trials (any EGFR mutation)
+2. Search mechanism-level trials (TKI trials)
+3. Check CIViC for any evidence on this specific variant
+4. Note variant rarity in report
+5. Suggest discussion with molecular tumor board
+
+### Multiple Biomarkers
+
+For complex molecular profiles:
+1. Search for each biomarker independently
+2. Search for combination biomarker trials
+3. Identify trials that require multiple biomarkers
+4. Score based on most actionable biomarker
+5. Flag potential synergistic drug targets
+
+### Conflicting Eligibility
+
+When patient meets some criteria but not others:
+1. Score partial match transparently
+2. Highlight which criteria are met/unmet
+3. Note if unmet criteria are waivable
+4. Suggest contacting PI for edge cases
+5. Provide alternative trials without conflicting criteria
+
+---
+
+## Known CIViC Gene IDs
+
+For direct CIViC lookups without search:
+
+| Gene | CIViC ID | Gene | CIViC ID |
+|------|----------|------|----------|
+| ALK | 1 | MET | 52 |
+| ABL1 | 4 | PIK3CA | 37 |
+| BRAF | 5 | ROS1 | 118 |
+| EGFR | 19 | RET | 122 |
+| ERBB2 | 20 | NTRK1 | 197 |
+| KRAS | 30 | NTRK2 | 560 |
+| TP53 | 45 | NTRK3 | 561 |
+
+---
+
+## Report File Naming Convention
+
+Save reports as:
+```
+clinical_trial_matching_[DISEASE]_[BIOMARKER]_[DATE].md
+```
+Example: `clinical_trial_matching_NSCLC_EGFR_L858R_2026-02-15.md`