@erosolaraijs/cure 2.3.0 → 2.4.0

package/src/capabilities/clinicalTrialMatchingModule.ts

@@ -0,0 +1,600 @@
+/**
+ * Clinical Trial Matching Engine
+ *
+ * ╔═══════════════════════════════════════════════════════════════════════════════╗
+ * ║  CLINICAL TRIAL MATCHING - CONNECTING PATIENTS TO NOVEL THERAPIES            ║
+ * ╠═══════════════════════════════════════════════════════════════════════════════╣
+ * ║  This module provides:                                                        ║
+ * ║  - Biomarker-to-trial mapping                                                ║
+ * ║  - Eligibility criteria assessment                                           ║
+ * ║  - Trial phase and mechanism matching                                        ║
+ * ║  - Geographic and logistical feasibility                                     ║
+ * ║  - Basket, umbrella, and platform trial navigation                           ║
+ * ╚═══════════════════════════════════════════════════════════════════════════════╝
+ */
+
+// ═══════════════════════════════════════════════════════════════════════════════
+// CLINICAL TRIAL DEFINITIONS
+// ═══════════════════════════════════════════════════════════════════════════════
+
+export interface ClinicalTrial {
+  nctId: string;
+  title: string;
+  phase: TrialPhase;
+  status: TrialStatus;
+  trialType: TrialType;
+  sponsor: string;
+  conditions: string[];
+  interventions: TrialIntervention[];
+  eligibilityCriteria: EligibilityCriteria;
+  locations: TrialLocation[];
+  biomarkerRequirements: BiomarkerCriterion[];
+  primaryEndpoint: string;
+  estimatedEnrollment: number;
+  studyStartDate: string;
+  estimatedCompletionDate: string;
+}
+
+export type TrialPhase = 'Early Phase 1' | 'Phase 1' | 'Phase 1/2' | 'Phase 2' | 'Phase 2/3' | 'Phase 3' | 'Phase 4';
+export type TrialStatus = 'Recruiting' | 'Active, not recruiting' | 'Enrolling by invitation' | 'Not yet recruiting' | 'Completed' | 'Suspended' | 'Terminated' | 'Withdrawn';
+export type TrialType = 'Interventional' | 'Basket' | 'Umbrella' | 'Platform' | 'Expanded Access';
+
+export interface TrialIntervention {
+  type: 'Drug' | 'Biological' | 'Device' | 'Radiation' | 'Procedure' | 'Combination';
+  name: string;
+  mechanism: string;
+  targetedPathway?: string;
+  novelty: 'First-in-class' | 'Next-generation' | 'Combination' | 'New indication';
+}
+
+export interface EligibilityCriteria {
+  ageRange: { min: number; max: number };
+  gender: 'All' | 'Male' | 'Female';
+  performanceStatus: { scale: 'ECOG' | 'Karnofsky'; maxValue: number };
+  priorTherapyRequirements: PriorTherapyRequirement[];
+  organFunctionRequirements: OrganFunctionRequirement[];
+  exclusionCriteria: string[];
+  inclusionCriteria: string[];
+}
+
+export interface PriorTherapyRequirement {
+  requirement: 'Required' | 'Allowed' | 'Excluded';
+  therapyType: string;
+  details: string;
+}
+
+export interface OrganFunctionRequirement {
+  organ: string;
+  parameter: string;
+  requirement: string;
+}
+
+export interface TrialLocation {
+  facility: string;
+  city: string;
+  state: string;
+  country: string;
+  status: 'Recruiting' | 'Not yet recruiting' | 'Completed';
+  contactName?: string;
+  contactPhone?: string;
+  contactEmail?: string;
+}
+
+export interface BiomarkerCriterion {
+  biomarker: string;
+  requirement: 'Required' | 'Preferred' | 'Excluded';
+  testMethod: string[];
+  details?: string;
+}
+
+// ═══════════════════════════════════════════════════════════════════════════════
+// TRIAL MATCHING CRITERIA
+// ═══════════════════════════════════════════════════════════════════════════════
+
+export interface PatientTrialProfile {
+  cancerType: string;
+  histology: string;
+  stage: string;
+  biomarkers: PatientBiomarker[];
+  priorTherapies: string[];
+  currentLine: number;
+  age: number;
+  performanceStatus: number;
+  organFunction: OrganFunctionStatus;
+  location: { country: string; state?: string; city?: string };
+  willingToTravel: boolean;
+  maxTravelDistance?: number; // miles
+  preferences: TrialPreferences;
+}
+
+export interface PatientBiomarker {
+  name: string;
+  status: 'Positive' | 'Negative' | 'Unknown';
+  value?: string | number;
+  method?: string;
+}
+
+export interface OrganFunctionStatus {
+  renalFunction: 'Normal' | 'Mild impairment' | 'Moderate impairment' | 'Severe impairment';
+  hepaticFunction: 'Normal' | 'Mild impairment' | 'Moderate impairment' | 'Severe impairment';
+  cardiacFunction: 'Normal' | 'Reduced' | 'Severely reduced';
+  bonemarrowFunction: 'Normal' | 'Reduced';
+}
+
+export interface TrialPreferences {
+  preferredPhases: TrialPhase[];
+  acceptPlaceboArm: boolean;
+  preferLocalTrials: boolean;
+  interestedMechanisms: string[];
+}
+
+export interface TrialMatch {
+  trial: ClinicalTrial;
+  matchScore: number;
+  matchDetails: MatchDetail[];
+  eligibilityStatus: 'Likely Eligible' | 'Possibly Eligible' | 'Likely Ineligible' | 'Need More Info';
+  barriers: string[];
+  nextSteps: string[];
+}
+
+export interface MatchDetail {
+  criterion: string;
+  status: 'Met' | 'Not Met' | 'Partial' | 'Unknown';
+  explanation: string;
+}
+
+// ═══════════════════════════════════════════════════════════════════════════════
+// TRIAL DATABASE (REPRESENTATIVE EXAMPLES)
+// ═══════════════════════════════════════════════════════════════════════════════
+
+export const TRIAL_DATABASE: ClinicalTrial[] = [
+  // EGFR-mutant NSCLC Trials
+  {
+    nctId: 'NCT04816214',
+    title: 'Amivantamab + Lazertinib vs Osimertinib in EGFR-Mutant NSCLC (MARIPOSA)',
+    phase: 'Phase 3',
+    status: 'Active, not recruiting',
+    trialType: 'Interventional',
+    sponsor: 'Janssen',
+    conditions: ['NSCLC', 'EGFR-mutant'],
+    interventions: [
+      { type: 'Combination', name: 'Amivantamab + Lazertinib', mechanism: 'EGFR-MET bispecific + EGFR TKI', novelty: 'Combination' }
+    ],
+    eligibilityCriteria: {
+      ageRange: { min: 18, max: 99 },
+      gender: 'All',
+      performanceStatus: { scale: 'ECOG', maxValue: 1 },
+      priorTherapyRequirements: [
+        { requirement: 'Excluded', therapyType: 'Prior EGFR TKI', details: 'No prior EGFR TKI for metastatic disease' }
+      ],
+      organFunctionRequirements: [
+        { organ: 'Renal', parameter: 'CrCl', requirement: '≥50 mL/min' },
+        { organ: 'Hepatic', parameter: 'AST/ALT', requirement: '≤3x ULN' }
+      ],
+      exclusionCriteria: ['Active brain metastases', 'Prior EGFR TKI', 'Interstitial lung disease'],
+      inclusionCriteria: ['EGFR exon 19 del or L858R', 'Metastatic NSCLC', 'Treatment-naive']
+    },
+    locations: [
+      { facility: 'MD Anderson Cancer Center', city: 'Houston', state: 'TX', country: 'USA', status: 'Recruiting' },
+      { facility: 'Memorial Sloan Kettering', city: 'New York', state: 'NY', country: 'USA', status: 'Recruiting' }
+    ],
+    biomarkerRequirements: [
+      { biomarker: 'EGFR exon 19 del or L858R', requirement: 'Required', testMethod: ['NGS', 'PCR', 'ctDNA'] }
+    ],
+    primaryEndpoint: 'Progression-free survival',
+    estimatedEnrollment: 1074,
+    studyStartDate: '2021-05',
+    estimatedCompletionDate: '2025-12'
+  },
+  // HER2+ Breast Cancer Trials
+  {
+    nctId: 'NCT04784715',
+    title: 'Trastuzumab Deruxtecan vs Physician Choice in HER2-low Breast Cancer (DESTINY-Breast06)',
+    phase: 'Phase 3',
+    status: 'Recruiting',
+    trialType: 'Interventional',
+    sponsor: 'Daiichi Sankyo',
+    conditions: ['Breast Cancer', 'HER2-low'],
+    interventions: [
+      { type: 'Biological', name: 'Trastuzumab Deruxtecan', mechanism: 'HER2-directed ADC', novelty: 'New indication' }
+    ],
+    eligibilityCriteria: {
+      ageRange: { min: 18, max: 99 },
+      gender: 'All',
+      performanceStatus: { scale: 'ECOG', maxValue: 1 },
+      priorTherapyRequirements: [
+        { requirement: 'Required', therapyType: 'Prior endocrine therapy', details: 'For HR+ patients' },
+        { requirement: 'Allowed', therapyType: 'Prior chemotherapy', details: '1-2 prior lines allowed' }
+      ],
+      organFunctionRequirements: [
+        { organ: 'Cardiac', parameter: 'LVEF', requirement: '≥50%' }
+      ],
+      exclusionCriteria: ['HER2-positive (IHC 3+)', 'History of ILD', 'Uncontrolled brain mets'],
+      inclusionCriteria: ['HER2-low (IHC 1+ or 2+/FISH-)', 'HR+ or HR-', 'Metastatic breast cancer']
+    },
+    locations: [
+      { facility: 'Dana-Farber Cancer Institute', city: 'Boston', state: 'MA', country: 'USA', status: 'Recruiting' }
+    ],
+    biomarkerRequirements: [
+      { biomarker: 'HER2-low', requirement: 'Required', testMethod: ['IHC', 'FISH'] }
+    ],
+    primaryEndpoint: 'Progression-free survival',
+    estimatedEnrollment: 850,
+    studyStartDate: '2021-03',
+    estimatedCompletionDate: '2026-06'
+  },
+  // KRAS G12C Trials
+  {
+    nctId: 'NCT04685135',
+    title: 'Sotorasib + Anti-EGFR in KRAS G12C CRC (CodeBreaK 300)',
+    phase: 'Phase 3',
+    status: 'Recruiting',
+    trialType: 'Interventional',
+    sponsor: 'Amgen',
+    conditions: ['Colorectal Cancer', 'KRAS G12C'],
+    interventions: [
+      { type: 'Combination', name: 'Sotorasib + Panitumumab', mechanism: 'KRAS G12C inhibitor + anti-EGFR', novelty: 'Combination' }
+    ],
+    eligibilityCriteria: {
+      ageRange: { min: 18, max: 99 },
+      gender: 'All',
+      performanceStatus: { scale: 'ECOG', maxValue: 1 },
+      priorTherapyRequirements: [
+        { requirement: 'Required', therapyType: 'Prior chemotherapy', details: '1-2 prior lines for metastatic disease' }
+      ],
+      organFunctionRequirements: [],
+      exclusionCriteria: ['Prior KRAS G12C inhibitor', 'Symptomatic brain mets'],
+      inclusionCriteria: ['KRAS G12C mutation', 'Metastatic CRC', 'Prior fluoropyrimidine, oxaliplatin, irinotecan']
+    },
+    locations: [
+      { facility: 'Multiple sites', city: 'Various', state: 'Various', country: 'USA', status: 'Recruiting' }
+    ],
+    biomarkerRequirements: [
+      { biomarker: 'KRAS G12C', requirement: 'Required', testMethod: ['NGS', 'PCR'] }
+    ],
+    primaryEndpoint: 'Overall survival',
+    estimatedEnrollment: 160,
+    studyStartDate: '2021-01',
+    estimatedCompletionDate: '2025-06'
+  },
+  // Basket Trial Example
+  {
+    nctId: 'NCT02465060',
+    title: 'NCI-MATCH: Targeted Therapy Directed by Genetic Testing (Basket Trial)',
+    phase: 'Phase 2',
+    status: 'Active, not recruiting',
+    trialType: 'Basket',
+    sponsor: 'NCI',
+    conditions: ['Solid Tumors', 'Lymphoma'],
+    interventions: [
+      { type: 'Drug', name: 'Multiple targeted agents', mechanism: 'Various - based on molecular alteration', novelty: 'First-in-class' }
+    ],
+    eligibilityCriteria: {
+      ageRange: { min: 18, max: 99 },
+      gender: 'All',
+      performanceStatus: { scale: 'ECOG', maxValue: 1 },
+      priorTherapyRequirements: [
+        { requirement: 'Required', therapyType: 'Prior standard therapy', details: 'Progressed on standard options' }
+      ],
+      organFunctionRequirements: [],
+      exclusionCriteria: ['Matched targeted therapy previously received'],
+      inclusionCriteria: ['Actionable genomic alteration', 'No standard treatment options']
+    },
+    locations: [
+      { facility: 'ECOG-ACRIN Network Sites', city: 'Multiple', state: 'Multiple', country: 'USA', status: 'Recruiting' }
+    ],
+    biomarkerRequirements: [
+      { biomarker: 'Actionable mutation per NCI-MATCH arms', requirement: 'Required', testMethod: ['NGS'] }
+    ],
+    primaryEndpoint: 'Overall response rate',
+    estimatedEnrollment: 6000,
+    studyStartDate: '2015-08',
+    estimatedCompletionDate: '2025-12'
+  },
+  // Immunotherapy Combination
+  {
+    nctId: 'NCT03899610',
+    title: 'Nivolumab + Relatlimab vs Nivolumab in Melanoma (RELATIVITY-047)',
+    phase: 'Phase 3',
+    status: 'Active, not recruiting',
+    trialType: 'Interventional',
+    sponsor: 'Bristol-Myers Squibb',
+    conditions: ['Melanoma'],
+    interventions: [
+      { type: 'Combination', name: 'Nivolumab + Relatlimab', mechanism: 'Anti-PD-1 + Anti-LAG-3', novelty: 'First-in-class' }
+    ],
+    eligibilityCriteria: {
+      ageRange: { min: 18, max: 99 },
+      gender: 'All',
+      performanceStatus: { scale: 'ECOG', maxValue: 1 },
+      priorTherapyRequirements: [
+        { requirement: 'Excluded', therapyType: 'Prior anti-PD-1/PD-L1', details: 'No prior checkpoint inhibitor' }
+      ],
+      organFunctionRequirements: [],
+      exclusionCriteria: ['Active autoimmune disease', 'Prior immunotherapy'],
+      inclusionCriteria: ['Unresectable or metastatic melanoma', 'Treatment-naive for metastatic disease']
+    },
+    locations: [
+      { facility: 'Multiple sites', city: 'Various', state: 'Various', country: 'USA', status: 'Recruiting' }
+    ],
+    biomarkerRequirements: [],
+    primaryEndpoint: 'Progression-free survival',
+    estimatedEnrollment: 714,
+    studyStartDate: '2019-04',
+    estimatedCompletionDate: '2024-12'
+  },
+  // CAR-T Trial
+  {
+    nctId: 'NCT04503278',
+    title: 'Cilta-cel vs Standard of Care in Multiple Myeloma (CARTITUDE-4)',
+    phase: 'Phase 3',
+    status: 'Active, not recruiting',
+    trialType: 'Interventional',
+    sponsor: 'Janssen',
+    conditions: ['Multiple Myeloma'],
+    interventions: [
+      { type: 'Biological', name: 'Ciltacabtagene autoleucel (Cilta-cel)', mechanism: 'BCMA-directed CAR-T', novelty: 'Next-generation' }
+    ],
+    eligibilityCriteria: {
+      ageRange: { min: 18, max: 99 },
+      gender: 'All',
+      performanceStatus: { scale: 'ECOG', maxValue: 1 },
+      priorTherapyRequirements: [
+        { requirement: 'Required', therapyType: 'Prior lenalidomide and PI', details: '1-3 prior lines including lenalidomide and a PI' }
+      ],
+      organFunctionRequirements: [
+        { organ: 'Cardiac', parameter: 'LVEF', requirement: '≥45%' },
+        { organ: 'Pulmonary', parameter: 'O2 sat', requirement: '≥92% on room air' }
+      ],
+      exclusionCriteria: ['Prior BCMA-targeted therapy', 'Active CNS involvement', 'Uncontrolled infection'],
+      inclusionCriteria: ['Relapsed/refractory MM', 'Lenalidomide-refractory', '1-3 prior lines']
+    },
+    locations: [
+      { facility: 'Multiple academic centers', city: 'Various', state: 'Various', country: 'USA', status: 'Recruiting' }
+    ],
+    biomarkerRequirements: [],
+    primaryEndpoint: 'Progression-free survival',
+    estimatedEnrollment: 400,
+    studyStartDate: '2020-06',
+    estimatedCompletionDate: '2026-01'
+  },
+  // Pediatric Trial
+  {
+    nctId: 'NCT03155620',
+    title: 'Larotrectinib in Pediatric Solid Tumors with NTRK Fusion (SCOUT)',
+    phase: 'Phase 1/2',
+    status: 'Recruiting',
+    trialType: 'Basket',
+    sponsor: 'Bayer',
+    conditions: ['Pediatric Solid Tumors', 'NTRK Fusion'],
+    interventions: [
+      { type: 'Drug', name: 'Larotrectinib', mechanism: 'TRK inhibitor', novelty: 'First-in-class' }
+    ],
+    eligibilityCriteria: {
+      ageRange: { min: 0, max: 21 },
+      gender: 'All',
+      performanceStatus: { scale: 'Karnofsky', maxValue: 50 },
+      priorTherapyRequirements: [
+        { requirement: 'Allowed', therapyType: 'Prior therapy', details: 'No limit on prior therapies' }
+      ],
+      organFunctionRequirements: [],
+      exclusionCriteria: ['Prior TRK inhibitor', 'Primary CNS tumor'],
+      inclusionCriteria: ['NTRK gene fusion', 'Relapsed or refractory solid tumor', 'Age ≤21']
+    },
+    locations: [
+      { facility: "Children's Hospital of Philadelphia", city: 'Philadelphia', state: 'PA', country: 'USA', status: 'Recruiting' },
+      { facility: 'Texas Childrens Hospital', city: 'Houston', state: 'TX', country: 'USA', status: 'Recruiting' }
+    ],
+    biomarkerRequirements: [
+      { biomarker: 'NTRK1/2/3 fusion', requirement: 'Required', testMethod: ['NGS', 'FISH', 'IHC'] }
+    ],
+    primaryEndpoint: 'Overall response rate',
+    estimatedEnrollment: 150,
+    studyStartDate: '2017-07',
+    estimatedCompletionDate: '2025-12'
+  }
+];
+
+// ═══════════════════════════════════════════════════════════════════════════════
+// TRIAL MATCHING ENGINE
+// ═══════════════════════════════════════════════════════════════════════════════
+
+export class ClinicalTrialMatchingEngine {
+  private trials: ClinicalTrial[] = TRIAL_DATABASE;
+
+  findMatchingTrials(patient: PatientTrialProfile): TrialMatch[] {
+    const matches: TrialMatch[] = [];
+
+    for (const trial of this.trials) {
+      if (trial.status === 'Withdrawn' || trial.status === 'Terminated') continue;
+
+      const matchResult = this.evaluateTrialMatch(patient, trial);
+      if (matchResult.matchScore > 0) {
+        matches.push(matchResult);
+      }
+    }
+
+    return matches.sort((a, b) => b.matchScore - a.matchScore);
+  }
+
+  private evaluateTrialMatch(patient: PatientTrialProfile, trial: ClinicalTrial): TrialMatch {
+    const matchDetails: MatchDetail[] = [];
+    const barriers: string[] = [];
+    let score = 0;
+
+    // Check cancer type match
+    const cancerMatch = trial.conditions.some(c =>
+      c.toLowerCase().includes(patient.cancerType.toLowerCase()) ||
+      patient.cancerType.toLowerCase().includes(c.toLowerCase())
+    );
+    if (cancerMatch) {
+      score += 30;
+      matchDetails.push({ criterion: 'Cancer type', status: 'Met', explanation: 'Cancer type matches trial conditions' });
+    } else {
+      matchDetails.push({ criterion: 'Cancer type', status: 'Not Met', explanation: 'Cancer type does not match' });
+    }
+
+    // Check biomarker requirements
+    for (const bioReq of trial.biomarkerRequirements) {
+      const patientBiomarker = patient.biomarkers.find(b =>
+        b.name.toLowerCase().includes(bioReq.biomarker.toLowerCase()) ||
+        bioReq.biomarker.toLowerCase().includes(b.name.toLowerCase())
+      );
+
+      if (bioReq.requirement === 'Required') {
+        if (patientBiomarker?.status === 'Positive') {
+          score += 25;
+          matchDetails.push({ criterion: `Biomarker: ${bioReq.biomarker}`, status: 'Met', explanation: 'Required biomarker is positive' });
+        } else if (patientBiomarker?.status === 'Negative') {
+          score -= 50;
+          barriers.push(`Required biomarker ${bioReq.biomarker} is negative`);
+          matchDetails.push({ criterion: `Biomarker: ${bioReq.biomarker}`, status: 'Not Met', explanation: 'Required biomarker is negative' });
+        } else {
+          matchDetails.push({ criterion: `Biomarker: ${bioReq.biomarker}`, status: 'Unknown', explanation: 'Biomarker status not tested' });
+        }
+      } else if (bioReq.requirement === 'Excluded') {
+        if (patientBiomarker?.status === 'Positive') {
+          score -= 50;
+          barriers.push(`Excluded biomarker ${bioReq.biomarker} is positive`);
+          matchDetails.push({ criterion: `Biomarker: ${bioReq.biomarker}`, status: 'Not Met', explanation: 'Excluded biomarker is positive' });
+        }
+      }
+    }
+
+    // Check age eligibility
+    const ageElig = trial.eligibilityCriteria.ageRange;
+    if (patient.age >= ageElig.min && patient.age <= ageElig.max) {
+      score += 10;
+      matchDetails.push({ criterion: 'Age', status: 'Met', explanation: `Age ${patient.age} within range ${ageElig.min}-${ageElig.max}` });
+    } else {
+      barriers.push(`Age ${patient.age} outside eligible range ${ageElig.min}-${ageElig.max}`);
+      matchDetails.push({ criterion: 'Age', status: 'Not Met', explanation: 'Age outside eligible range' });
+    }
+
+    // Check performance status
+    const psReq = trial.eligibilityCriteria.performanceStatus;
+    if (patient.performanceStatus <= psReq.maxValue) {
+      score += 10;
+      matchDetails.push({ criterion: 'Performance status', status: 'Met', explanation: `PS ${patient.performanceStatus} meets requirement ≤${psReq.maxValue}` });
+    } else {
+      barriers.push(`Performance status ${patient.performanceStatus} exceeds maximum ${psReq.maxValue}`);
+      matchDetails.push({ criterion: 'Performance status', status: 'Not Met', explanation: 'Performance status too high' });
+    }
+
+    // Check phase preference
+    if (patient.preferences.preferredPhases.includes(trial.phase)) {
+      score += 5;
+    }
+
+    // Check location
+    const matchingLocation = trial.locations.find(loc =>
+      loc.country === patient.location.country &&
+      loc.status === 'Recruiting'
+    );
+    if (matchingLocation) {
+      score += 10;
+      matchDetails.push({ criterion: 'Location', status: 'Met', explanation: `Trial available in ${matchingLocation.city}, ${matchingLocation.state}` });
+    } else if (patient.willingToTravel) {
+      score += 5;
+      matchDetails.push({ criterion: 'Location', status: 'Partial', explanation: 'Patient willing to travel' });
+    } else {
+      barriers.push('No recruiting sites in patient location');
+      matchDetails.push({ criterion: 'Location', status: 'Not Met', explanation: 'No local sites; travel required' });
+    }
+
+    // Determine eligibility status
+    let eligibilityStatus: TrialMatch['eligibilityStatus'];
+    if (barriers.length === 0 && score > 50) {
+      eligibilityStatus = 'Likely Eligible';
+    } else if (barriers.length === 0) {
+      eligibilityStatus = 'Need More Info';
+    } else if (barriers.some(b => b.includes('Required biomarker') || b.includes('Age'))) {
+      eligibilityStatus = 'Likely Ineligible';
+    } else {
+      eligibilityStatus = 'Possibly Eligible';
+    }
+
+    // Generate next steps
+    const nextSteps: string[] = [];
+    if (eligibilityStatus === 'Likely Eligible' || eligibilityStatus === 'Possibly Eligible') {
+      nextSteps.push('Discuss with oncologist');
+      nextSteps.push(`Contact trial site: ${trial.locations[0]?.facility || 'See ClinicalTrials.gov'}`);
+      nextSteps.push(`Search ClinicalTrials.gov for NCT: ${trial.nctId}`);
+    }
+    if (matchDetails.some(m => m.status === 'Unknown')) {
+      nextSteps.push('Complete biomarker testing');
+    }
+
+    return {
+      trial,
+      matchScore: Math.max(0, score),
+      matchDetails,
+      eligibilityStatus,
+      barriers,
+      nextSteps
+    };
+  }
+
+  findTrialsByBiomarker(biomarker: string): ClinicalTrial[] {
+    return this.trials.filter(trial =>
+      trial.biomarkerRequirements.some(b =>
+        b.biomarker.toLowerCase().includes(biomarker.toLowerCase())
+      )
+    );
+  }
+
+  findTrialsByMechanism(mechanism: string): ClinicalTrial[] {
+    return this.trials.filter(trial =>
+      trial.interventions.some(i =>
+        i.mechanism.toLowerCase().includes(mechanism.toLowerCase())
+      )
+    );
+  }
+
+  findBasketTrials(): ClinicalTrial[] {
+    return this.trials.filter(trial => trial.trialType === 'Basket');
+  }
+
+  findPediatricTrials(): ClinicalTrial[] {
+    return this.trials.filter(trial =>
+      trial.eligibilityCriteria.ageRange.min < 18 ||
+      trial.conditions.some(c => c.toLowerCase().includes('pediatric'))
+    );
+  }
+
+  getTrialById(nctId: string): ClinicalTrial | undefined {
+    return this.trials.find(t => t.nctId === nctId);
+  }
+
+  generateTrialSearchStrategy(patient: PatientTrialProfile): {
+    searchTerms: string[];
+    recommendedDatabases: string[];
+    searchTips: string[];
+  } {
+    const searchTerms: string[] = [
+      patient.cancerType,
+      patient.histology,
+      ...patient.biomarkers.filter(b => b.status === 'Positive').map(b => b.name)
+    ];
+
+    return {
+      searchTerms,
+      recommendedDatabases: [
+        'ClinicalTrials.gov (clinicaltrials.gov)',
+        'NCI Cancer Clinical Trials (cancer.gov/clinicaltrials)',
+        'TrialMatch (lls.org/support/information-specialists)',
+        'EmergingMed Navigator (emergingmed.com)'
+      ],
+      searchTips: [
+        'Use condition + biomarker for targeted searches',
+        'Filter by "Recruiting" status',
+        'Check Phase 1/2 trials for novel mechanisms',
+        'Consider basket trials if you have an actionable mutation',
+        'Contact trial coordinators directly for eligibility questions'
+      ]
+    };
+  }
+}
+
+// Export singleton
+export const clinicalTrialMatchingEngine = new ClinicalTrialMatchingEngine();