Regulatory Perspectives on NGS-based CDx

1 14thDIA Japan Annual Meeting 2017 November 12-14, 2017 | Tokyo Big Sight | AriakeReiko Yanagihara, of In Vitro DiagnosticsDeputy Review DirectorPharmaceuticals and Medical Devices AgencyRegulatory Perspectives on NGS-based CDxDisclaimerThe views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to DIA, its directors, officers, employees, volunteers, members, chapters, councils, Communities or affiliates, or any organization with which the presenter is employed or PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. DIA and the DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners.

2 2017 DIA, Inc. All rights CDxRegulatory Framework of NGS-based IVDE valuation of NGS-based CDxNGS-based Oncology Panel 2017 DIA, Inc. All rights 2017 DIA, Inc. All rights in Japan: Nucleic Acid-Based CDxCDxTrade NameDrugTrade Name (INN)POTELIGEO TEST IHCPOTELIGEO TEST FCMPOTELIGEO(Mogamulizumab)VysisALK BreakApart FISH probe kitXalkori(crizotinib) ALECENSA (alectinib)HistofineALK iAEPkitALECENSA (alectinib)CobasBRAF V600mutation testZelboraf(vemurafenib)THxIDBRAFkitTaf inlar(dabrafenib)Mekinist(trametinib)Cob asEGFR mutation test (osimertinib)OncoGuideAmoyDxROS1 Gene Fusions Detection KitXalkori(crizotinib)PD-L1 IHC 22C3 pharmDx[Dako]KEYTRUDA(pembrolizumab)IVDs to detect RAS mutation, HER2 gene amplificationand EGFR mutation are also used to guide therapies with a corresponding therapeutic product. Next Generation Sequencing-based CDxCase2In case where several genes should be analyzed to choose the suitable therapeutic product for a specific indicationCase1In case where various variants of a gene should be analyzed for treatment with the targeted therapy( BRCA1/2gene variants)gene A variantApproved DrugAApproved DrugBApproved DrugCgeneCvariantgeneBvariant Regulatory Status of NGS-based CDxinUS 2017 DIA, Inc.

3 All rights Guidance Use of public DB Use of Stds< NGS-based CDx>FoundationFocusCDxBRCA<NGS-basedCDx>OncomineDxTarget TestMultiple analytby single testNOT by NGSBRACA nalysisCDx< NGS-based CDx>PraxisExtendedRASpanelRegulatory Status of NGS-based CDxinUS 2017 DIA, Inc. All rights Generation Sequencing-based CDx 2017 DIA, Inc. All rights multiple therapeutic products and comprehensive gene profilinggene A variantApproved DrugAApproved DrugBApproved DrugCComprehensive Genomic ProfilinggeneCvariantgeneBvariant Reporting of variantsto guide therapies?EvolutionofNucleic Acid Based-CDx 2017 DIA, Inc. All rights Drug1 CDx trastuzumaband HER2 test)1 Drug multiple CDx( EGFR-TKI and EGFR mutation test)Multiple Drug multiple CDxNon-CDx Oncology panel)MultipleDrug 1 CDxsystem BRCA test)1 Drug multiple-variant testingOutlineNGS-based IVDR egulatory Framework of NGS-based IVDE valuation of NGS-based CDxNGS-based Oncology Panel 2017 DIA, Inc.

4 All rights 2017 DIA, Inc. All rights and Administrative notice on Nucleic Acid Based Test using DNA sequencer201520162017 Legislation Notice on DNA sequencer based-IVDQ&AIssuedatetitleApr 28,2016 LegislationNotice to Applicants for Marketing Authorization of DNA Sequencers and Related Products Utilized for Genetic Testing SystemsJan 26,2017 Questionsand Answers on Marketing Authorization of DNA Sequencers and Related Products Utilized for Genetic Testing SystemsJuly, 2016 Concept paper: Evaluation policy of the companion diagnostic systems using next generation sequencing (draft) paper on NGS-based CDxNotification and Administrative Notice on Nucleic Acid Based Test using DNA sequencerRegulatory framework of DNAsequencer-based IVD 2017 DIA, Inc. All rights acid extractionreferenceDatabaseClass III IVDR eagents for library constructionSoftwareReagents for sequencing sample II MDClass IIor III MDDNA sequencer-based IVD system(combination MD)Questionsrelated to Administrative Notice issued on Jan 26, 2017 2017 DIA, Inc.

5 All rights for library constructionToReagents for sequencing sample Class II MD, MAA is MD DNA seqshould be specified. Performancecharacteristics and spec of DNA seqshould be sequencerOutlineNGS-based IVDR egulatory Framework of NGS-based IVDE valuation of NGS-based CDxNGS-based Oncology Panel 2017 DIA, Inc. All rights 2017 DIA, Inc. All rights of NGS-based CDx Basic principles are the same as conventional CDx. CDxshould provide accurate and reproducible results. CDxshould be able to identify a population expected to benefit from the therapeutic. Validation approach considering the characteristic feature of NGS-based system could be possible. 2017 DIA, Inc. All rights Validation Clinical specimen should be used in principle. Use of contrived sample For rare variants, use of contrived sample could be acceptable. Appropriateness of the contrived sample should be shown based on the commutability study.

6 Pan-tumor claim A range of specimens should be evaluated. Effect of variations in sample preparation and pre-analytical methods should be evaluated. Quality metrics Depth of coverage Quality Score, etc. 2017 DIA, Inc. All rights Validation Representativevalidationapproach It is acceptable to validate representative subset of variants including contrived sample if scientific rationale is appropriately provided. Representative subset of variants should cover the range of variants to be detected by the system. Variant types(SNV, indels, fusions, etc.) Variant sizes( ) Genomic context (GC-rich regions, homopolymericregions, etc.)Analytical Validation: Observed issues 2017 DIA, Inc. All rights Insufficient consideration on pre-analytical metrics Acquisitionmethods( fineneedlebiopsy,surgicalbiopsy) Fixation condition for FFPE tumor tissue specimens Insufficient quality control of DNA or RNA specimen No acceptance criteria for DNA or RNA qualityClinical Performance of NGS-based CDx 2017 DIA, Inc.

7 All rights cases where the variant classification is crucial for the eligibility of the therapy Validity of classification criteria and classification process should be demonstrated. Variant classification will be evaluated taking into consideration the following aspects: Genotype-pathogenesis correlation and the mechanism of action of the therapeutic product Rationale for the classification criteria based on scientific evidence Robustness of the classification process CDxwith the same intended use as the approved CDx 2017 DIA, Inc. All rights : Clinical performance of the proposed CDxshould be comparable to the approved CDx. Concordance between the approved CDxand the proposed CDxshould be reasonably high. If clinical performance of the proposed CDxcannot be ensured by the concordance study, clinical performance should be evaluated as a stand-alone CDx. CDxwith the same intended use and the specimen type as the approved CDxOutlineNGS-based IVDR egulatory Framework of NGS-based IVDE valuation of NGS-based CDxNGS-based Oncology Panel 2017 DIA, Inc.

8 All rights sequencerDNA dataOutput:List of annotated variants Oncology PanelSoftwareExample1: Analytical flow using Oncology PanelFurther Analysis by Expert Panel?Intended UseEvaluation of Clinical Utilityin Japanese medical settingApproved as IVD?Physician22 Clinical validity of each geneGenotype-pathogenesis correlation based on: guideline/guidance Public DB, ,indel,CNV,fusion/translocationVariant callReference seqProprietary DBAdditional info on possible therapyExternal DBpathogenicBenignUncertain significanceCriteria for clinical evidence?ReportPatient ID: xxxxxvarantsxxxInterpretationxxxEDNA dataOutput:List of annotated variants Oncology PanelSoftwareExample2: Analytical flow using Oncology PanelIntended UseApproved as IVD?23 Clinical validity of each geneGenotype-pathogenesis correlation based on: guideline/guidance Public DB, ,indel,CNV,fusion/translocationVariant callReference seqpathogenicBenignUncertain significanceDNA sequencingAnnotation Patient ID: xxxxxGenetic aberrations:AKT1E17K Evaluation of Clinical Utilityin Japanese medical settingReportPatient ID: xxxxxvarantsxxxInterpretationxxxAddition al info on possible therapyExternal DBExternal DBPhysicianCriteria for clinical evidence?

9 Further Analysis by Expert Panel? 2017 DIA, Inc. All rights for PMDA: Genes/variants for non-CDxuse Intended use Clinical validity of genes on a panel Coverage of genes/variants Criteria for clinical validity As a measure of tumormutational burdenHow many genes are enough? Analyticalvalidation Interpretation of gene variants detected Should DB be specified? What levels of evidence should be considered? Implementation into medical setting Correct use and interpretation of an panel by end-usersAMED projecton Evaluation of NGS-based IVD 2017 DIA, Inc. All rights Representative researcher: Dr. KenjiroKosaki, KeioUniversitySchool of Medicine 2017-2019FY Research Goal: Guidance development on: Analytical validation of NGS-based IVD Points to consider on the use of public DB for NGS-based IVD development 2017 DIA, Inc. All rights Intended use Clinical validity of genes on a panel Coverage of genes/variants Criteria for clinical validity As a measure of tumormutational burdenHow many genes are enough?

10 Analyticalvalidation Interpretation of gene variants detected Should DB be specified? What levels of evidence should be considered? Implementation into medical setting Correct use and interpretation of an panel by end-usersChallenges for PMDA: Genes/variants for non-CDxuseAcknowledgement 2017 DIA, Inc. All rights of CDxWG and Office of IVDin PMDAAsk