PK n\_rels/PK n\ docProps/PK n\ppt/PK n\ ppt/_rels/PK n\ ppt/charts/PK n\ppt/charts/_rels/PK n\ppt/embeddings/PK n\ ppt/media/PK n\ppt/slideLayouts/PK n\ppt/slideLayouts/_rels/PK n\ppt/slideMasters/PK n\ppt/slideMasters/_rels/PK n\ ppt/slides/PK n\ppt/slides/_rels/PK n\ ppt/theme/PK n\ppt/notesMasters/PK n\ppt/notesMasters/_rels/PK n\ppt/notesSlides/PK n\ppt/notesSlides/_rels/PK n\LU%)%)[Content_Types].xml PK n\]] _rels/.rels PK n\nؔttdocProps/app.xml 0 0 Microsoft Office PowerPoint On-screen Show (16:9) 0 20 20 0 0 false Fonts Used 2 Theme 1 Slide Titles 20 Arial Calibri Office Theme Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20 PptxGenJS false false false 16.0000 PK n\OOdocProps/core.xml PptxGenJS Presentation PptxGenJS Presentation PptxGenJS PptxGenJS 1 2026-07-15T16:35:28Z 2026-07-15T16:35:28Z PK n\bbppt/_rels/presentation.xml.rels PK n\Oݨ ppt/theme/theme1.xmlPK n\[Qppt/presentation.xml PK n\Xppt/presProps.xml PK n\ppt/tableStyles.xml PK n\D >00ppt/viewProps.xml PK n\H7t!ppt/slideLayouts/slideLayout1.xml PK n\ђ77,ppt/slideLayouts/_rels/slideLayout1.xml.rels PK n\4Wppt/slides/slide1.xml KCLG MEDICAL EDUCATION SERIESCompanion Diagnosticsin OncologyRegulatory Framework · Analytical & Clinical Validation · CDx Co-DevelopmentNGS Platforms · Liquid Biopsy · Landmark Case StudiesKCLEAGENICS MEDICAL INC. · kclgmedical.com · July 2026PK n\3 ppt/slides/_rels/slide1.xml.rels PK n\yKPFFppt/notesSlides/notesSlide1.xml Welcome to Companion Diagnostics in Oncology — a comprehensive review at PhD level. This deck covers the full CDx landscape from regulatory framework through to emerging frontiers.1PK n\:A*ppt/notesSlides/_rels/notesSlide1.xml.rels PK n\kZ 77ppt/slides/slide2.xml FOUNDATIONSWhat Is a Companion Diagnostic?Definition (FDA, 21 CFR Part 809)"An in vitro diagnostic (IVD) device or imaging tool that provides information ESSENTIAL for the safe and effective use of a corresponding therapeutic product."Key word: ESSENTIAL→ Drug cannot be safely prescribed without a positive CDx result→ CDx result required in prescribing information (drug label)Companion DiagnosticResult REQUIRED before drug useRegulated as Class III Device — PMA pathwayMust be co-developed and co-submitted with drugComplementary DiagnosticResult USEFUL but not mandatoryMay use 510(k) or De Novo pathwayDrug can be prescribed without positive resultPK n\2- ppt/slides/_rels/slide2.xml.rels PK n\՘<<ppt/notesSlides/notesSlide2.xml A CDx is legally required before the drug can be prescribed. This is the "essential" test — contrasted with complementary diagnostics where testing is optional.2PK n\xշ*ppt/notesSlides/_rels/notesSlide2.xml.rels PK n\UTzF@F@ppt/slides/slide3.xml MARKET OVERVIEWCDx in Numbers: A Rapidly Growing Field50+FDA-ApprovedCDx Devices(as of 2025)$10BGlobal CDxMarket Value(2024)~$19BProjectedMarket Value(2030)2×Phase III SuccessRate: Biomarker-Selected vs. All-ComersFirst CDx Approval: HercepTest (1998) · First NGS Panel CDx: FoundationOne CDx (2017) · First Liquid Biopsy CDx: cobas EGFR Plasma (2016)Sources: FDA CDx List (updated Feb 2026); Grand View Research CDx Market Report 2024; DiMasi et al., Biomarker-selected trial success ratesPK n\W/ ppt/slides/_rels/slide3.xml.rels PK n\A &22ppt/notesSlides/notesSlide3.xml The CDx market is one of the fastest-growing segments in diagnostics, driven directly by the pipeline of biomarker-defined oncology drugs. ~18% CAGR through 2030.3PK n\9 Y*ppt/notesSlides/_rels/notesSlide3.xml.rels PK n\ >>ppt/slides/slide4.xml REGULATORY FRAMEWORKFDA Regulation: PMA Under 21 CFR Part 80901Class III DeviceCDx classified as highest-risk device. Requires Premarket Approval (PMA) — most rigorous FDA device pathway. Regulated by CDRH.02Co-DevelopmentDrug (CDER) and CDx (CDRH) developed and reviewed simultaneously. Cross-agency coordination required. Joint advisory committees in some cases.03PMA SubmissionDossier includes: analytical performance data, device description, software validation (for NGS), clinical data showing biomarker-by-treatment interaction.04Co-ApprovalCDx approved contemporaneously with drug NDA/BLA. CDx result required in prescribing information before patient receives drug.PK n\` ppt/slides/_rels/slide4.xml.rels PK n\feeppt/notesSlides/notesSlide4.xml Class III designation means CDx carries the highest risk classification — paralleling the drug's potential to harm patients if given to the wrong population. PMA requires human clinical data, unlike 510(k).4PK n\J *ppt/notesSlides/_rels/notesSlide4.xml.rels PK n\zjAOAOppt/slides/slide5.xml CDX SCIENCEAnalytical Validation: Proving the Device WorksParameterDefinitionOncology ImplicationDiagnostic Sensitivity% of truly positive specimens correctly identified as positiveLow sensitivity → eligible patients denied treatment. FDA scrutinises sensitivity in enrichment CDx.Diagnostic Specificity% of truly negative specimens correctly identified as negativeLow specificity → biomarker-negative patients receive drug without evidence of benefit — toxicity without gain.Precision: RepeatabilityReproducibility same operator, instrument, dayWithin-run variation must not cross patient-classification threshold (e.g., IHC 3+ boundary).Precision: ReproducibilityAcross operators, instruments, labs, daysCritical for IHC (subjective scoring) and NGS (bioinformatics pipeline variation). Multi-site data required.PK n\5 ppt/slides/_rels/slide5.xml.rels PK n\ɦ]766ppt/notesSlides/notesSlide5.xml Analytical validation answers: does this device accurately and reproducibly measure the biomarker? Without this foundation, clinical validity data is uninterpretable.5PK n\Qe*ppt/notesSlides/_rels/notesSlide5.xml.rels PK n\0,::ppt/slides/slide6.xml CDX SCIENCEClinical Validation: Proving the Biomarker Predicts BenefitThe Biomarker-by-Treatment InteractionClinical validity requires a STATISTICALLY SIGNIFICANT INTERACTION between biomarker status and treatment effect.This is NOT the same as showing biomarker-positive patients have better outcomes (that is a prognostic biomarker).Predictive = differential treatment benefit by statusPrognostic = outcome regardless of treatmentThe Cutoff Selection ProblemMany biomarkers are continuous variables:· PD-L1 Tumour Proportion Score (TPS) 0–100%· HER2 copy number ratio· TMB (mutations per megabase)Cutoff too HIGH:Excludes patients who would benefit — reducescommercial reach; denies therapy to patients.Cutoff too LOW:Includes non-responders — dilutes observedefficacy signal; misleading regulatory data.PK n\ج+ ppt/slides/_rels/slide6.xml.rels PK n\sXllppt/notesSlides/notesSlide6.xml Clinical validity is the hardest part. It requires trial data showing the biomarker-by-treatment interaction — not just that positive patients do better, but that they benefit MORE from the drug than negative patients.6PK n\=|*ppt/notesSlides/_rels/notesSlide6.xml.rels PK n\]^^ppt/slides/slide7.xml CDX DEVELOPMENTCDx Co-Development TimelinePre-INDDrugIdentify molecular target; biomarker hypothesis from preclinical dataCDxCandidate biomarker assay selection; CDx partner identification; FDA pre-IND biomarker discussionPhase IDrugSafety/PK; dose escalation; biomarker expansion cohort if early signals emergeCDxEvaluate candidate assay on Phase I specimens; begin analytical development; feasibility testingPhase IIDrugInitial efficacy; define biomarker-positive population; proof-of-conceptCDxLock prototype CDx assay; complete analytical performance package; begin CDRH pre-submission meetingsPhase IIIDrugRandomised confirmatory trial; CDx used as inclusion criterionCDxCommercial-intent assay in pivotal trial; accumulate PMA data; submit PMA parallel with NDA/BLAPK n\F ppt/slides/_rels/slide7.xml.rels PK n\yf==ppt/notesSlides/notesSlide7.xml Late-stage CDx development is the most common cause of drug-CDx approval misalignment. Early alignment — from Phase I onward — is essential for contemporaneous approval.7PK n\|g*ppt/notesSlides/_rels/notesSlide7.xml.rels PK n\%(,IIppt/slides/slide8.xml CASE STUDY 1 / HER2 & TRASTUZUMABThe Original CDx: HercepTest & Herceptin (1998–2024)Timeline of the HER2/CDx Story· 1998 — HercepTest (IHC, Dako) approved as first-ever FDA CDx alongside trastuzumab (Herceptin) for HER2+ metastatic breast cancer· 2001 — Slamon et al. (NEJM): trastuzumab + chemo improved OS 20.3 → 25.1 months (p=0.046) in IHC 3+ or FISH+ patients· 2007 — ASCO/CAP guidelines revealed up to 20% of "HER2-positive" patients may have been misclassified — wrong treatment, wrong denial· 2012 — Multiple HER2 assay platforms (IHC 3+, FISH ratio ≥2.0, ISH) in simultaneous use across countries with different cutoffs· 2017 — FoundationOne CDx approved as pan-tumour NGS CDx for HER2 (ERBB2) amplification· 2023 — ASCO/CAP update added HER2-low category (IHC 1+, or IHC 2+/ISH-) for trastuzumab deruxtecan (T-DXd) — a new patient population invisible to the original binary frameworkBiomarkerERBB2 amplificationor protein overexpressionCDx DevicesHercepTest IHC · PathVysion FISH · FoundationOne CDxDrug (NDA/BLA)Trastuzumab BLA 103792Plus 10+ HER2-targeted agentsKey LessonCDx complexity can persist for decades. New CDx categories can open new patient populations 25 years post-approval.PK n\6 ppt/slides/_rels/slide8.xml.rels PK n\Puppt/notesSlides/notesSlide8.xml The HER2/trastuzumab story is the most instructive in CDx history. It illustrates how CDx complexity can accumulate over time, how misclassification at scale affects patients, and how a new CDx category (HER2-low) can open a previously invisible patient population decades after initial approval.8PK n\pO*ppt/notesSlides/_rels/notesSlide8.xml.rels PK n\\Uuuppt/slides/slide9.xml CASE STUDY 2 / EGFR & OSIMERTINIBSequential CDx Development: 1st to 3rd Generation EGFR TKI1st GenDrugErlotinibGefitinibCDxcobas EGFR v1(tissue: Ex19del, L858R)OutcomePFS ~9-11 moAll patients develop resistance2nd GenDrugAfatinibCDxcobas EGFR v2(tissue: Ex19del, L858R)OutcomePFS ~11-13 mo~60% acquire T790MT790MCDxDrugPlasma CDxFirst in ClassCDxcobas EGFR v2PLASMA — T790M(2016, first liquid biopsy CDx)OutcomePlasma sensitivity:~70-75% vs tissue gold standard3rd GenDrugOsimertinib(Tagrisso)CDxcobas EGFR v2 (tissue + plasma)FoundationOne CDxGuardant360 CDx (plasma)OutcomeFLAURA: PFS 18.9 vs 10.2 moHR 0.46 (p<0.001)Gold standard 1LPK n\>$ ppt/slides/_rels/slide9.xml.rels PK n\Jxxppt/notesSlides/notesSlide9.xml The EGFR/osimertinib case is the best example of sequential CDx development. Each therapeutic generation required a new CDx — and the T790M CDx in plasma was a watershed moment, establishing liquid biopsy as a viable CDx platform.9PK n\1*ppt/notesSlides/_rels/notesSlide9.xml.rels PK n\e2NNppt/slides/slide10.xml CASE STUDY 3 / BRCA & PARP INHIBITORSGermline vs. Somatic CDx: BRACAnalysis CDx and FoundationOne CDxOlaparib (Lynparza) CDx Approvals2014Ovarian CancerBRACAnalysis CDx (germline) | BRCA1/2 mutations2018Breast CancerBRACAnalysis CDx (germline) | BRCA1/2 mutations2019Pancreatic CancerBRACAnalysis CDx (germline) | BRCA1/2 mutations2020mCRPC (Prostate)BRACAnalysis CDx + FoundationOne CDx | BRCA1/2 (germline)HRR panel (somatic — 14 genes)Germline (BRACAnalysis CDx)Whole blood DNA — detects inherited BRCA1/2 variants. First CDx based on germline testing. Submitted by Myriad Genetic Laboratories. Approved 2014 (P140020).Somatic (FoundationOne CDx)Tumour tissue DNA — detects somatic BRCA1/2 + all HRR gene alterations (14 genes in mCRPC). Enables treatment for the ~5-7% with somatic-only BRCA mutations. Same drug (olaparib), different CDx, different patient population.PK n\Ѳ!ppt/slides/_rels/slide10.xml.rels PK n\An/DD ppt/notesSlides/notesSlide10.xml The BRCA/PARP inhibitor landscape shows how a single biomarker can drive approvals across multiple tumour types, and how germline and somatic testing create parallel CDx pathways.The BRCA CDx landscape is the clearest example of how a biomarker evolves across indications. Note the addition of the full HRR panel (14 genes) for mCRPC — not just BRCA1/2 — which required a different CDx device (FoundationOne CDx) for the same drug.10PK n\T+ppt/notesSlides/_rels/notesSlide10.xml.rels PK n\$Ybbppt/slides/slide11.xml CASE STUDY 4 / PD-L1 & PEMBROLIZUMABContinuous Biomarker Complexity: PD-L1 IHC and TMBIndicationRequired CDxThreshold / NoteNSCLC 1L MonotherapyPD-L1 IHC 22C3 pharmDxTPS ≥50% (~30% of NSCLC qualify)NSCLC 1L + Chemo ComboPD-L1 IHC 22C3 pharmDxTPS ≥1%Cervical Cancer 2L MonoPD-L1 IHC 22C3 pharmDxTPS ≥1%MSI-H / dMMR Tumours(any histology)MMR IHC (local) or validated PCRNo PD-L1 test required — histology-agnosticTMB-High Solid Tumours(any histology)FoundationOne CDxTMB ≥10 mut/Mb — first pan-tumour genomic CDx (2020)Key insight: For the same drug, 5 different testing approaches — different assays, different thresholds, different biological rationales.PK n\;!ppt/slides/_rels/slide11.xml.rels PK n\#DD ppt/notesSlides/notesSlide11.xml Pembrolizumab has the most complex CDx profile in oncology — because the required test and threshold differ by tumour type, line of therapy, and whether it is mono or combo therapy.The PD-L1 pembrolizumab case is the most operationally complex CDx scenario in oncology today. Site staff and CRAs must know which CDx and which threshold applies to the specific pembrolizumab indication being studied — these are not interchangeable.11PK n\O+ppt/notesSlides/_rels/notesSlide11.xml.rels PK n\o=x=xppt/slides/slide12.xml NGS PLATFORM CDXFoundationOne CDx: The Pan-Tumour NGS Paradigm324cancer-related genesanalysed in one test+ TMB status+ MSI status+ Genomic signaturesApproved: Nov 2017 (P170019)Foundation Medicine / RocheEGFR Ex19del / L858RNSCLCOsimertinib, Erlotinib, Gefitinib, AfatinibALK rearrangementsNSCLCAlectinib, Crizotinib, CeritinibBRAF V600ENSCLC, MelanomaDabrafenib + TrametinibERBB2 (HER2) amplificationBreast, GastricTrastuzumab, Pertuzumab, T-DM1BRCA1/2 alterationsMulti-tumourOlaparib (ovarian, breast, prostate, pancreatic)PIK3CA mutationsHR+/HER2- BreastAlpelisib (Piqray)MET exon 14 skippingNSCLCCapmatinib (Tabrecta)TMB ≥10 mut/MbAll solid tumoursPembrolizumab (Keytruda)PK n\c!ppt/slides/_rels/slide12.xml.rels PK n\5}ϛ ppt/notesSlides/notesSlide12.xml FoundationOne CDx (P170019, approved Nov 2017) transformed the CDx landscape by consolidating multiple single-analyte assays into a single pan-tumour NGS panel that can serve as CDx for multiple drugs simultaneously.FoundationOne CDx approval fundamentally changed CDx economics and logistics. A single tissue sample can now determine eligibility for multiple drugs across multiple biomarkers. The approval process for each new biomarker/drug pair is a PMA supplement (S-number), building on the original P170019 approval.12PK n\Fb+ppt/notesSlides/_rels/notesSlide12.xml.rels PK n\^OAOAppt/slides/slide13.xml LIQUID BIOPSYctDNA Liquid Biopsy as Companion DiagnosticHow ctDNA Liquid Biopsy CDx WorksTumour cells shed DNA fragments into blood circulation (ctDNA). A blood draw detects tumour mutations without tissue biopsy.FDA-APPROVED LIQUID BIOPSY CDx:Guardant360 CDx (Guardant Health)EGFR Ex19del / L858R in plasmaFor 1st-line osimertinib in NSCLCcobas EGFR Mutation Test v2 (Roche)EGFR T790M in plasmaFor 2nd-line osimertinib post-TKIAdvantages· Minimally invasive (blood draw)· Captures tumour heterogeneity from multiple sites· Repeatable — tracks mutation evolution during treatment· Valuable when tissue is insufficient, inaccessible, or high-riskKey Limitations· Reduced sensitivity in early-stage disease (low shedding)· False-negative rate up to 30% in stage I–II NSCLC· Fusions/amplifications less reliably detected in plasma· NEGATIVE result does NOT exclude mutation → Tissue biopsy must follow (plasma-first, tissue-reflex)PK n\x!ppt/slides/_rels/slide13.xml.rels PK n\/4tt ppt/notesSlides/notesSlide13.xml Liquid biopsy CDx eliminates the need for tissue biopsy in appropriate settings. Key limitation: a negative plasma result does NOT exclude the mutation. Always specify a tissue-reflex algorithm in clinical trials.Critical operational point for trial teams: a negative Guardant360 CDx result in plasma does NOT make a patient ineligible. Protocol must specify reflex to tissue biopsy CDx. A positive plasma result IS sufficient for eligibility in the approved osimertinib indications.13PK n\yv+ppt/notesSlides/_rels/notesSlide13.xml.rels PK n\YNbzzppt/slides/slide14.xml TRIAL DESIGN IMPLICATIONSBiomarker Trial Design: Enrichment, Stratification & InteractionEnrichment DesignWhen to UseStrong prior evidence of differential benefit in biomarker+ patients; rare biomarker requiring central testingRegulatoryRequires prospective validated CDx at screening; FDA expects parallel CDx development pathwayAdvantagesSmaller sample size; more efficient efficacy detection; less exposure of likely-non-responders to drug toxicityLimitationsCannot formally test biomarker-by-treatment interaction; limits label to tested population onlyAll-Comers with StratificationWhen to UseHypothesised differential benefit but insufficient evidence for enrichment; biomarker prevalence high enough to enrol both groupsRegulatoryPre-specify biomarker subgroup in SAP; powered on overall population; subgroup hypothesis-generating unless poweredAdvantagesCan generate interaction test data; broader eligibility; pragmatic intent-to-treat effect estimableLimitationsRequires larger sample size; biomarker-negative patients receive drug without expected benefitBiomarker-Stratified DesignWhen to UseGenuine equipoise about benefit in biomarker-negative patients; want formal test of interactionRegulatoryComplex multiplicity adjustment required; hierarchical testing procedures specified in protocolAdvantagesFull interaction test powered; potential for two separate label claims (BM+ and BM-)LimitationsLargest sample size requirement; most complex statistical plan; less common in modern oncologyPK n\O!ppt/slides/_rels/slide14.xml.rels PK n\ԉ ppt/notesSlides/notesSlide14.xml The CDx strategy determines trial design. Enrichment designs are operationally simpler but cannot formally demonstrate the biomarker-by-treatment interaction required for CDx clinical validation. All-comers designs can test the interaction but require larger sample sizes.Slide for PIs and regulatory colleagues. The choice of enrichment vs. all-comers design determines not just the statistical plan but the type of evidence generated for CDx validation. Enrichment designs cannot provide the interaction test data needed for standalone CDx clinical validation.14PK n\?ݤ+ppt/notesSlides/_rels/notesSlide14.xml.rels PK n\](??ppt/slides/slide15.xml GLOBAL REGULATIONCDx Regulation Beyond FDA: EMA, PMDA, NMPAUnited States (FDA)21 CFR Part 809 · Class III · PMA pathway · CDRH review · Contemporaneous approval with drug (CDER) · ~600 day review targetMost established CDx framework globallyEuropean Union (EMA/IVDR)EU IVDR 2017/746 · Full effect from 2022 · Notified Body review (not direct EMA) · Higher evidence standard than prior IVDD · Companion diagnostics designated as Class C or D devicesSignificant regulatory step-change from old IVDDJapan (PMDA)Simultaneous regulatory review (SAKIGAKE) introduced 2014 · CDx reviewed by PMDA alongside drug · Bridging study often required for assay equivalence · Japanese-specific population data may be requiredAlignment with FDA/EMA increasing but Japan-specific data commonChina (NMPA)CDx regulated under medical device framework · Domestic clinical data often required · Increasing alignment with ICH guidelines since 2017 ICH membership · Complex regulatory environment for global submissionsRapidly evolving; local clinical data requirement remains key barrierPK n\*R!ppt/slides/_rels/slide15.xml.rels PK n\Ҧ ppt/notesSlides/notesSlide15.xml Global CDx development must account for parallel regulatory pathways that may differ substantially in evidence requirements and approval timelines. A US-approved CDx does not automatically satisfy European, Japanese, or Chinese requirements.For global oncology trials, the CDx regulatory strategy must account for multiple simultaneous pathways. The EU IVDR transition (2022) was particularly impactful — previously CE-marked IVDs required full re-evaluation under the new framework with substantially higher evidence requirements.15PK n\$Q+ppt/notesSlides/_rels/notesSlide15.xml.rels PK n\e{{ppt/slides/slide16.xml CLINICAL TRIAL OPERATIONSCDx Readiness Checklist for Trial TeamsHIGHCDx vs. trial assay alignmentAssay used for enrolment = commercial CDx or validated as equivalent by bridging studyHIGHLocal vs. central testing definedProtocol specifies which result governs eligibility; both cannot override the other without protocol definitionHIGHPre-analytical requirements trainedArchival tissue age, fixation duration, tumour content %, fresh biopsy criteria — all site staff trainedMEDTurnaround time complianceCDx TAT consistent with screening window; contingency procedure for exceedances documentedHIGHNegative result algorithmPlasma ctDNA negative → tissue reflex procedure specified; eligibility determination documentedMEDScreen failure documentationCDx result recorded for all screen failures — essential for biomarker prevalence estimation and protocol reviewMEDTissue banking and consent coverageResidual CDx specimens banked; consent covers future biomarker research; chain of custody maintainedHIGHRegulatory alignment confirmedPre-IND/Type B meeting confirms FDA accepts the proposed CDx for this trial; documented in INDPK n\ !ppt/slides/_rels/slide16.xml.rels PK n\ӻ ppt/notesSlides/notesSlide16.xml This checklist is directly applicable to site initiation, monitoring visits, and protocol deviation prevention. CDx-related screen failures and eligibility errors are among the most common FDA inspection findings in biomarker-enriched trials.This checklist is adapted from FDA inspection findings in biomarker-enriched oncology trials. The most common CDx-related deficiencies in FDA site inspections: using an unvalidated local assay for eligibility determination, missing screen failure CDx documentation, and inadequate tissue pre-analytical training.16PK n\ y+ppt/notesSlides/_rels/notesSlide16.xml.rels PK n\g ? ?ppt/slides/slide17.xml EMERGING FRONTIERSBeyond Today's CDx: Where the Field Is Going01Multi-Omic CDxIntegrating genomic, transcriptomic, proteomic, and epigenomic biomarkers into a single predictive algorithm. FDA's AI/ML Device Action Plan provides an emerging framework for algorithm-based CDx approval.02MRD as CDx EndpointMinimal residual disease (MRD) detection as a CDx endpoint for adjuvant therapy decisions. FDA draft guidance (2020) on MRD in haematologic malignancies; solid tumour applications in development.03AI-Powered Digital PathologyAI image analysis of standard H&E slides to extract biomarker information without additional staining or molecular testing. Multiple pre-submissions with FDA ongoing; spatial transcriptomics integration next step.04ctDNA ExpansionctDNA CDx approval expanding beyond EGFR/NSCLC to BRAF, KRAS, and pan-cancer biomarkers. Tumour-informed ctDNA MRD assays (personalised) creating new approval pathway discussions with FDA.PK n\檋!ppt/slides/_rels/slide17.xml.rels PK n\mm ppt/notesSlides/notesSlide17.xml These frontiers represent the next wave of CDx development. AI-based digital pathology CDx is currently in FDA pre-submission discussions. MRD as a regulatory endpoint has draft FDA guidance in haematologic malignancies.17PK n\BI+ppt/notesSlides/_rels/notesSlide17.xml.rels PK n\J]y>y>ppt/slides/slide18.xml KEY TAKEAWAYSCompanion Diagnostics: What Every OncologyResearcher Needs to Know1CDx ≠ optional testing. The word "essential" in the FDA definition has legal force — a drug cannot be prescribed without a positive CDx result.2Analytical validity and clinical validity are both required. A device can accurately detect a mutation (analytical) but fail if that mutation doesn't predict differential benefit (clinical).3Simultaneous co-development is not optional. Late-stage CDx development is the most common cause of drug-CDx approval misalignment — start the CDx programme in Phase I.4NGS panels (FoundationOne CDx) can serve as CDx for multiple drugs simultaneously — but each drug/biomarker combination requires its own PMA supplement approval.5A negative liquid biopsy result does NOT exclude the mutation. Every protocol using plasma CDx must specify a tissue-reflex algorithm.6PD-L1 and TMB are not interchangeable biomarkers. The required assay, threshold, and clinical rationale differ by indication — even within pembrolizumab alone.PK n\Yh!ppt/slides/_rels/slide18.xml.rels PK n\[1 ppt/notesSlides/notesSlide18.xml Summary slide for closing. Emphasise the co-development point — it is the single biggest operational lever. Companies that start CDx development late consistently face delays at submission. Also emphasise the liquid biopsy caveat — it is a frequent protocol deviation trigger in the field.18PK n\N+ppt/notesSlides/_rels/notesSlide18.xml.rels PK n\WE??ppt/slides/slide19.xml REFERENCESReferences & Regulatory Sources1. FDA. In Vitro Companion Diagnostic Devices — Guidance for Industry and Food and Drug Administration Staff. August 2014 (updated 2016). FDA.gov2. FDA. List of Cleared or Approved Companion Diagnostic Devices (IVD and Imaging Tools). fda.gov/medical-devices/in-vitro-diagnostics. Updated February 2026.3. 21 CFR Part 809 — In Vitro Diagnostics General Regulations. FDA Code of Federal Regulations.4. EU IVDR 2017/746 — Regulation on in vitro diagnostic medical devices. European Parliament and Council, 2017.5. Slamon DJ et al. Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer. NEJM. 2001;344(11):783–792.6. Ramalingam SS et al. (FLAURA). Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. NEJM. 2020;382:41–50.7. Mok TS et al. (PACIFIC extended data). Osimertinib or Platinum-Pemetrexed in p.T790M-Positive Lung Cancer. NEJM. 2017;376:629–640.8. DiMasi JA et al. Success Rates for New Drugs Entering Clinical Testing in the United States. Clin Pharmacol Ther. 2010;87(3):272–277.9. Foundation Medicine FoundationOne CDx PMA P170019 (and supplements). FDA CDRH Database.10. Guardant Health. Guardant360 CDx. PMA P200010. FDA Approval 2022.11. Myriad Genetics BRACAnalysis CDx. PMA P140020 (and supplements). FDA CDRH Database.12. Wolchok JD et al. iRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143–e152.13. Merck & Co. Keytruda (pembrolizumab) Prescribing Information. 2024. FDA-approved labelling.14. FDA. Project Optimus: Dose Optimization in Oncology Drug Development. FDA.gov/oncology. 2022.PK n\~!ppt/slides/_rels/slide19.xml.rels PK n\cmR ppt/notesSlides/notesSlide19.xml All regulatory sources are publicly available on FDA.gov and ICH.org. 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