Global Regulatory Landscape of Drug - Companion diagnostics and Revision Proposal of Domestic Guideline

Global Regulatory Landscape of Drug - Companion diagnostics and Revision Proposal of Domestic Guideline 동반진단의약품의해외규제현황및국내가이드라인제안 Young Kee Shin, M.D., Ph.D. College of Pharmacy, Seoul National University N-BIO (Institutes of Entrepreneurial BioConvergence), LOGONE Bio Convergence Research Foundation

Paradigm shift : Precision Medicine Precision Diagnostics Patient-first medical care Essential tool Patient:Subject of Healthcare Information Patient InformationDB Healthcare Democratization Regulation Scientification New developed diagnosis test Scientific evidence Patient Safety APPROVED REJECTED Payer-first medical care Risk / Efficacy Cost / Utility

Contents 1. Definition of Companion diagnostics (CDx) 2. Global Regulatory trend 3. Korea Regulatory trend 4. Current Regulatory issues in Korea 5. Suggestion

1. Definition of Companion Diagnostics

A Real World Example of Biomarker Application Biomarker HERCEPTIN IHC/FISH CISH Gleevec 1992 1997 1998 1999 2000 2001 2002 +3 (Memb. strong) IHC IUO (Herceptest) State Rituxan Phase I IND for rhumab HER2 +2 (<10% memb. strong) Joint CBER/ CDRH Mtg. BLA & PMA Filed +1 (Cytoplasmic) 0 Herceptin & HercepTest Approved Simultaneously FISH (Gene Amplification) sbla & spma Filed FISH spma Approved Herceptin Chromosomal Treatment Analysis FISH sbla Approved IHC 5

Approved CDx (U.S) for Herceptin Approved CDx (FDA) Company Biomarker Drug Platform HER2 FISH PharmDx Kit Dako Denmark A/S Her2/neu Herceptin, Perjeta, Kadcyla Fluorescence in situ hybridization (FISH) HERCEPTEST Dako Denmark A/S Her2/neu Herceptin, Perjeta, Kadcyla Immunohistochemical assay (IHC) HER2 CISH PharmDx Kit Dako Denmark A/S Her2/neu Herceptin Chromogenic In Situ Hybridization (CISH) INFORM HER2 DUAL ISH DN Chromogenic In Situ Hybridization Ventana Medical Systems Her2/neu Herceptin A Probe Cocktail (CISH) PATHWAY ANTI-HER-2/NEU (4 B5) Rabbit Monoclonal Primary Ventana Medical Systems Her2/neu Herceptin immunohistochemical assay (IHC) Antibody INFORM HER-2/NEU Ventana Medical Systems Her2/neu Herceptin Fluorescence in situ hybridization (FISH ) Bond Oracle Her2 IHC System Leica Biosystems Her2/neu Herceptin Immunohistochemical assay (IHC) SPOT-LIGHT HER2 CISH Kit Life Technologies Her2/neu Herceptin Chromogenic In Situ Hybridization (CISH) and brightfield microscopy INSITE HER-2/NEU KIT Biogenex Laboratories Her2/neu Herceptin immunohistochemical assay (IHC) PATHVYSION HER-2 DNA Pro be Kit FoundationOne CDx Assay Abbott Her2/neu Herceptin Foundation Medicine EGFR EGFR T790M ALK BRAF HER2 KRAS BRCA1/BRCA2 Gilotrif, Irresa, Tarceva Tagrisso Alecensa, Xalkori, Zykadia Tafinlar, Mekinist, Zelboraf, Cotellic Herceptin, Kadcyla, Perjeta Erbitux, Vectibix Rubraca Fluorescence in situ hybridization (FISH ) NGS

Definition of Companion diagnostics A companion diagnostics is a medical device, which provides information that is essential for the safe and effective use of a corresponding drug or biological product. The test helps a health care professional determine whether a particular therapeutic product s benefits to patients will outweigh any potential serious side effects or risks. Dx s (IVD) Qualitative yes for no to the presence of the biomarker Minor variation in sensitivity between lots, runs, locations do not change the overall test outcome CDx s (IVD Class III) Generally quantitative by nature (only those patients with expression above a threshold (cut-off) are eligible for treatment Minor variations in sensitivity between lots, runs, locations may change the test outcome IVD (IVD class I) Histology CDx-IVD (IVD class III) YES ( Yes it s a carcinoma ) YES ( Yes it s a carcinoma ) YES ( Yes it s a carcinoma ) No ( Its NOT a carcinoma, but a different tumor type ) xxxx xxx xx +400 Positive (above cut-off) Eligible for drug X +300 Borderline (around cut-off) Re-test +200 Negative (below cut-off) Not eligible for drug X 0 Negative (below cut-off) Not eligible for drug X 7

Unfavorable discordance - Increase of Drug development for Targeted therapies - Test increase of detection / measure of biomarker for investigation of Intention to Treat population Discordant result -> accurate, reproducible and clinically useful companion diagnostic test

What is Precision Medicine? U.S. FDA Guidance Personalized medicine (also referred to as Precision medicine ) relies on the use of in vitro diagnostic (IVD) devices to detect and measure biomarkers and other individual characteristics of disease or other conditions with the goal of better directing patient treatment. Document issued on: Dec.18, 2017 9

What is Precision Medicine? U.S. FDA Guidance - When accurate testing for molecular alterations is essential for the safe and effective use of the drug, an FDA-cleared or -approved assay should be commercially available at the time of drug approval to identify patients in the clinical setting. Document issued on: Dec.18, 2017 - The FDA may grant exceptions when the drug is intended to treat a serious or life-threatening condition for which no satisfactory alternative treatment exists, and FDA determines that the benefits from the use of the drug outweigh the risks from the lack of an approved or cleared in vitro companion diagnostic device. 10

Diagnostics utility (CDx vs. IVD, LDT) - Laboratory Developed Test - Homebrew Test - IVD - Complementary Dx without Predictive power - Complementary Dx with Predictive power LDT IVD CDx Analytical Validity Minimal Yes Yes Clinical Validity No Yes Reagent Quality Management S ystem with Clinical cut-off No Yes Yes On-Going Proficiency Testing Yes No No Pre-Market Data Review No Yes Yes - Companion Diagnostics - Single Lab PMA - Follow-on CDx Product Labeling Requirements No Yes Yes Post Market Adverse Event rep orting No Yes Yes Lab Personnel Qualifications Yes No No Transparency of Clinical Test performance No Yes Yes

LDT vs. IVD-CDx LDT Reagents Manufacturing & Quality Management system * Intended use Regulator IVD-CDx FFPE Block Instruments - Who? Will be tested? - What? Are the appropriate specimens? FFPE Block - How? Test results? DNA extraction System (including S/W) GMP (ISO13485) Facilities * Device Performance - Analytical performance Reliability and accuracy DNA extraction IVD Mutation detection (by qpcr) LDT Evidence & Evidence Level considered * Analytical Validity or Performance * Cost-effective * Clinical Validity or Performance * Clinical Utility IVD - Clinical performance Clinical sensitivity and specificity positive and negative predictive values - Labeling Intended use, device design, directions for use, warnings/limitations, result interpretation, performance Tx Mutation detection (by qpcr) Software algorithm No Tx CDx

2. Global Regulatory Trend

U.S regulatory Overview Currently, about 36 companion diagnostic tests for valid genomic biomarkers are approved in the United States. The Food and Drug Administration (FDA) is focused on the co-development of the drug diagnostic approach. Companion diagnostic products are classified as Class III high risk and are subject to approval by the FDA. Source: Frost & Sullivan

Drug and companion diagnostic co-development process (U.S) IVD-CDx development process Regulatory concept : Co-approval (exceptions will exist) Co-development Benefits Evaluate drug and device in one trial Regulatory Pathway for companion Diagnostics: Drug vs CDx approval process US Source: The center for anti companion diagnostics modification

Comparison of regulatory pathway for CDx US EU China Japan Korea Risk Classification Device Classification Class I Class A Class I Class I Class I Little or no Risk Class II Class III Class B Class II Class II Class II Class C Class III Class III Class III Class D Class IV Class IV Medium Risk High Risk

Definition of CDx in Japan A CDx is essential for using the pertinent therapeutic product, and corresponds to either of the following (except in vitro diagnostic agents or medical devices intended simply for disease diagnosis, etc.) : CDx is used to identify patients who are expected to respond better to a specific therapeutic product CDx is used to identify patients who are likely to be at high risk of developing adverse events associated with a particular therapeutic product CDx is necessary for optimizing the treatment including dose, schedule, and discontinuation of a particular therapeutic product Notification on Approval Application for In-vitro companion diagnostics and corresponding therapeutic products Source: T. Suzuki, National institute of Health science

Comparison of regulatory pathway for CDx Definition of CDx Labeling Requirments Biomarkernegative patients US EU Japan (i) to identify patients most likely to benefit from a therapeutic product, and (ii) to identify patients likely to be at an increased risk for serious adverse reactions as a result of treatment with the therapeutic product, and (iii) to monitor response to treatment with the therapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness. To identify patients in the population for whom the therapeutic product X has been adequately studied, and found safe and effective. In addition to the drug labeling inform ation about sets of companion diagnosti None of the products contained a reference to a specific companion diagnostic cs placed on the corresponding therapeuproduct in the therapeutic indication. tic product. Inclusion of biomarker-negative patients in early-phase clinical trials is mentioned more clearly in the Japanese guidance than in the US guidance or EU draft guidance. Retrospective vs. prospective clinical trials The Japanese guidance goes further, uniquely highlighting prospectively designed retrospective three exceptional cases in which it may be difficult to clinical utility studies may be possible. conduct prospective randomized controlled trials. Nature biotechnology, vol34, no.2, Feb 2016

Comparison of regulatory pathway for CDx (continued) The Japanese guidance goes further, uniquely highlighting three exceptional cases in which it may be difficult to conduct prospective randomized controlled trials. First, cases in which running a trial would be questionable on ethical grounds because patients who have a biomarker are subject to extremely serious adverse events when the corresponding therapeutic is administered. Second, cases in which running a trial would be questionable on practical grounds because too few patients in a population carry the biomarker of interest and thus the patient cohort in the trial would be too small. Third, cases in which evaluation of the biomarker on the basis of retrospective analyses is valid even after considering potential biases that arise from such post factum studies.

Pathway to CE marking of companion diagnostics (E.U) Pathway to CE marking of companion diagnostics under the current legal framework and possible scenario under proposed new legal framework under discussion. Clin Cancer Res 2014;20:1458-1468.

E.U regulatory trend Class C Medical device.. CE Marking CE Medical Device IVD-CDx should be classified as Class C Update on safety and clinical implication report / year 21

New rules for IVDs, EU The set of rules covering IVDs will take effect in 2022, The new rules, the EC said, will improve "market surveillance and traceability" and ensure that all IVDs and medical devices are designed "to reflect the latest scientific and technology state of the art." Additionally, they will create more transparency for consumers and certainty for manufacturers of such products, while strengthening international competitiveness and innovation. Also, a financial mechanism will be created to ensure that patients who have been harmed by defective medical devices will be financially compensated. 22

3. Korea Regulatory Trend

Medical device classification in korea Medical devices in Korea are regulated by the Ministry of Food and Drug Safety (MFDS). Manufacturers must follow the requirements of the Medical Devices Act and register with the MFDS before entering the Korean market. Source: MFDS, Korea

in Korea Oct. 2015 MFDS IVD-CDx Guideline (Doc#_B1-2015-5-238) Currently, the development and approval of new drug and companion diagnostics have been conducted separately in Korea. The companion diagnostics in Korea have labels to show the safety and effectiveness of drugs. However, the labels on the drug does not specify companion diagnostics but refer to biomarker test including homebrew assay. Because the accuracy of diagnostics has a great influence on patients in the case of high-risk therapeutic drugs, a strict regulation system of diagnostic products is essential for the benefit of patient and payers.

Follow-on CDx Analytical validation Same gene/variant level validation as original CDx Published Summary of Safety and Effectiveness Data (SSED) as reference Method comparison with approved CDx No drug trial required Banked samples from intended use population Requirement for preservation of drug efficacy Variability between follow-on CDx and originally approved CDx should be within the variability of originally approved CDx

Follow-on CDx (Approval, Health insurance review process in Korea) Before Current: One Stop service (rev. Aug.2014) MFDS Submission of medical device for approval (80 day) NECA New Health Technology Assessment (360 day) HIRA Assessment of item Tech (New or existing HIRA Health insurance review (150 day) MFDS Submission of medical device for approval HIRA Assessment of item Tech (New or existing Tech.) NECA New Health Technology Assessment Tech.) 80 Day 280 Day HIRA Health insurance review (150 day) 440 Day 360 Day 150 Day Item approval - MFDS: Ministry of Food and Drug Safety - NECA: National Evidence-based Healthcare Collaborating Agency - HIRA: Health Insurance Review & Assessment Service First Follow-on CDx in Korea Item approval GenesWell ddegfr mutation test 150 Day Companion Diagnostics for NSCLC patient with EGFR mutation Companion Drugs: TARCEVA (Erlotinib) 46 mutation sites of EGFR gene through 4-well Possible detection with a small amount of DNA (3.3ng/well) Possible with low-frequency mutation (FFPE, about 0.8% )

Follow-on CDx Non-inferiority Test (US) vs Equivalence Test (Korea) Terms: CCD: Comparator companion diagnostic FCD: Follow-on Companion diagnostic To support the identical therapeutic indications as CCD, the safety and effectiveness of FCD and CCD should be comparable. There are two approaches: New clinical trial Retest of patients samples from the original clinical trial While the two approaches above are ideal, they may be difficult or impractical to follow. Suggestion: External concordance study to evaluate the clinical performance of FCD when the direct estimate of the therapeutic efficacy in FCD s intented use population is not feasible. Source: Statistics in Biopharmaceutical Research 8.3 (2016): 355-363.

Korean regulation on CDx Asian Harmonization Working Party (AHWP) adopted Korea's companion In-vitro diagnostics Based on Korea s in-vitro companion diagnostics device guideline.. Guidance for Additional Considerations to support Conformity Assessment of Companion In vitro Diagnostic Medical Devices(AHWP/WG2/F001:2017) <Sep. 2017>

Current Issue.. Drug Label (Tagrisso) Tagrisso US EU Japan Korea Approval Date 2015 2016 2016 2016 Indicated Use Non-small cell lung cancer (NSCLC) EGFR T790M mutation-positive NSCLC. EGFR T790M mutation- Positive NSCLC Non-small cell lung cancer (NSCLC) Warning & Precautions EGFR T790M mutation positive NSCLC, as detected by an FDA approved test EGFR mutation status should be determined using a validated test method EGFR T790M mutation tests p erformed by a thoroughly expe rienced pathologist or testing laboratory. Approved IVDs should be us ed for the test. EGFR T790M status should be determined using a validated test method In Australia A validated test should be performed in a clinical laboratory using either tumor tissue DNA or circulating tumor DNA (ctdna) obtained from a blood (plasma) sample. Only robust, reliable and sensitive test(s) with demonstrated utility for the determination of EGFR mutation status should be used (see CLINICAL TRIALS_eg.Cobas EGFR test) Korea : It is not specified on the label of the drug. It is not necessary. U.S, Japan : Always use approved CDx for prescription of drugs. It is specified on the label of the drug.

4. Current regulatory issues in Korea - Risk of Homebrew Assay - Unfavorable Discordance - NGS Issue

PARP inhibitor license 2011 Foundation Medicine s NGS-based CDx Collaboration 2007- license 2012 acquisition 2006 Rucaparib BRACAnalysis CDx mychoice HRD license 2012 Olaparib Niraparib license 2015 collaboration acquisition license Talazoparib Veliparib

PARP inhibitor CDx Germline BRCA1/2 mutation Germline BRCA1/2 mutation Somatic BRCA1/2 mutation Germline BRCA1/2 mutation Somatic BRCA1/2 mutation HRD score

PARPi (olaparib) and CDx (Myriad) U.S Approved Japan E.U Korea Mostly Germline BRCA variant Homebrew test (Laboratory developed test??, LDT in US) Patient Safety?? Single Lab PMA concept Drug CDx Intended use Lynparza (olaparib) BRACAnalysis CDx BRACAnalysis CDx is an in vitro diagnostic device intended for the qualitative detection a nd classification of variants of BRCA1 and BRCA2 genes. Results of the test are used as an aid in identifying ovarian cancer patients treatment with Lynparza (olaparib). This assay is fo r professional use only and is to be performed only at Myriad Genetic Laboratories, a single lab oratory site located at 320 Wakara Way, Salt Lake City, UT 84108.

Homebrew BRCA assay in Korea - False Positive Issue : Interpretation for Deleterious mutation - False Negative Issue : Detection Primer/Probe, Technology, Interpretation Can BRCAAnalysisCDx be used in Korea? - Can BRCAAnalysisCDx reflect the ethnic difference? - Reasonable test : analytical validity and clinical validity - Who should judge the validity? - Drug Risk = Assay Risk

FoundationFocus CDx BRCA LOH Rubraca clinical trial

Rubraca issues in korea 1. How check the somatic BRCA alteration? MFDS in Korea 2. If.. Home-brew assay is used in Korea.. Unfavorable Discordance issue

High risk of LDT Nov. 2015, FDA pointed out the Risk of Laboratory Developed Test 38

Why CDx pursues IVD * Poor Concordance Between Local and Central laboratory HER2 testing A total of 1,198 breast carcinoma samples were collected from 6 institutions in Korea. Of the 1,198 samples, 959 (80%) samples for local IHC, central IHC were analyzed Bae et al., 2012 Interlaboratory concordance in HER2 status The results of local and central IHC were consistent for 783 samples, with a concordance rate of 81.6% Of the 211 samples with a local IHC result of positive, 140 (66.4%) samples were concordant with a central IHC results. 39 E.A. Perez et al. / Cancer Treatment Reviews 40 (2014) 276 284

LDT vs. FDA-approved assay Are there performance differences between laboratory-developed tests (LDTs) and US Food and Drug Administration approved companion diagnostics (FDA-CDx)? 1. Lack of no. of specimens 2. Different proportions of specimens using LDT and FDA-approved kit 3. Through the results of just three mutations, can not represent other complicated test methods The risk of LDT still exists.. JAMA Oncol. doi:10.1001/jamaoncol.2017.4021

Who Have the responsibility of the risk of homebrew assay in Korea? MFDS vs Ministry of Health and Welfare vs Medical Doctor Patients only - Patients right to select Diagnosis - Can patients use an overseas diagnostic laboratory that provides services with CDx products because their clinical evidence level is higher? - If the government or physician does not inform the patient of this fact, is this not a significant infringement of the patient's rights?

Risk of Homebrew assay Laboratory Developed Test In U.S.. Ongoing FDA has established and continues to implement a unique device identification system to adequately identify medical devices through their distribution and use. When fully implemented, the label of most devices will include a unique device identifier (UDI) in human- and machinereadable form. - Adverse effects to patients caused by diagnostic errors - Who take responsibility?? Doctor? Lab? Regulatory Body? - It is impossible to trace the diagnostic errors. - Can you trust the results? - In the case of NGS, different SW &DB are used, so the results may differ.

CDx for CRC patients U.S Approved CDx Korea Apporved only IVD in Korea IVD vs Homebrew test (Sanger)?? High Risk False negative issue due to Low sensitivity (15%) U.S. (CDx) The test is intended to be used as an aid in the identification of CRC patients who should not be treated with Erbitux (cetuximab) or with Vectibix (panitumumab) when KRAS Codon 12 or 13 mutation is detected. Korea (IVD) The cobas KRAS Mutation Test, for use with the cobas 4800 System, is a real-time PCR test intended for the identification of mutations in codons 12, 13 and 61 of the KRAS gene in DNA derived from FFPE human colorectal cancer tissues.

Approved CDx (U.S) in Erbitux an Vectibix Korean IVD vs RUO in Korea but approved CDx in US Approved CDx (FDA) Company Biomarker Drug Platform DAKO EGFR PharmDx KIT Dako, North America EGFR Erbitux therascreen KRAS RGQ PCR Kit Qiagen KRAS The cobas KRAS Mutation Test Roche KRAS Erbitux Vectibix Erbitux Vectibix Praxis Extended RAS Panel Illumina KRAS, NRAS Vectibix immunohistochemical assa y (IHC) Real-time PCR Real-time PCR Targeted high throughput parallel sequencing (NGS) FoundationOne CDx Assay Foundation Medicine EGFR Gilotrif, Irresa, Tarceva NGS EGFR T790M ALK BRAF HER2 KRAS BRCA1/BRCA2 Tagrisso Alecensa, Xalkori, Zykadia Tafinlar, Mekinist, Zelboraf, Cotellic Herceptin, Kadcyla, Perjeta Erbitux, Vectibix Rubraca

CDx vs. Complementary Dx Drug name Keytruda (Pembrolizumab) Tecentriq (Atezolizumab) Opdivo (Nivolumab) Clinical Design Dx Product PD-L1 IHC 22C3 pharmdx (Dako) Ventana PD-L1 IHC SP142 (Roche) PD-L1 IHC 28-8 pharmdx (Dako) Approval condition Intended use CDx PD-L1 IHC 22C3 pharmdx is indicated as an aid in identifying NSCLC patients for treatment with KEYTRUDA (pembrolizumab).. Complementary Dx w/ Predictive power PD-L1 expression in 50% TC or 10% IC determined by VENTANA PD-L1 (SP142) Assay in NSCLC tissue may be associated with enhanced overall survival from TECENTRIQ (atezolizumab). Complementary Dx w/o Predictive power PD-L1 IHC 28-8 pharmdx in nonsquamous NSCLC may be associated with enhanced survival from OPDIVO (nivolumab).

Blueprint PD-L1 IHC Assay Comparison Project Different Antibody

Blueprint PD-L1 IHC Assay Comparison Project PD-L1 expression was evaluable with all assays in 493 samples. The three assays showed similar patterns of tumor membrane staining, with high correlation between percent PD-L1 staining. An overall percentage agreement of >90% was achieved between assays at multiple expression cutoffs, including 1%, 10%, 25%, and 50% tumor membrane staining. Clin Cancer Res. 2017 Jul 15;23(14):3585-3591. 47

Current issue (PD-L1 assay) 28-8 Intended Use Korea U.K U.S Non-squamous non-small cell lung cancer Non-squamous NSCLC / SCCHN / Melanoma / Urothelial carcinoma (UC) Non-squamous non-small cell lung cancer (NSCLC) / Melanoma tissues Drug OPDIVO (nivolumab) OPDIVO (nivolumab) OPDIVO (nivolumab) SP263 Intended Use Non-small cell lung cancer/keytruda Non-squamous NSCLC/OPDIVO NSCLC (KEYTRUDA)/ Non-squamous NSCLC patients (OPDIVO)/ Urothelial carcinoma (IMFINZI) Urothelial carcinoma (UC) Drug KEYTRUDA (pembrolizumab) OPDIVO (nivolumab) KEYTRUDA (pembrolizumab) OPDIVO (nivolumab) IMFINZI (durvalumab) IMFINZI (durvalumab) Intended used of Ventana SP263 kit (MFDS) May.2018 48

Drug and companion diagnostic co-development May, 2017 KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instabilityhigh (MSI-H) or mismatch repair deficient (dmmr) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established. 49

FDA approves first cancer treatment for any solid tumor with a specific genetic feature

Tumor Mutation Burden (TMB): cut-off issue Source: https://www.predicine.org - Tumor Mutation Burden (TMB) is the total number of mutations per coding area of a tumor genome. - Higher TMB levels are correlated with higher levels of neo-antigens which help our immune system to recognize tumors. - TMB can be measured by tumor genomic profiling assay, as predictor of response to Immune checkpoint therapy.

NGS for Insurance beneficiaries with diseases (in Korea) Germline Variants Somatic Variants Hereditary Diseases Solid tumor Hematology malignancy Coverage (Diseases) Hereditary retinitis pigmentosa Hereditary bradyecoia CharcotMarie Tooth syndrome Hereditary disorders excluding the above three diseases Gastric Cancer, Lung Cancer, Colorectal Cancer, Breast Cancer, Ovarian Cancer, Melanoma, Gastrointesrinal stromal tumor, Celebro-spinal cord malignant tumor, Pediatric neuroblastoma, Cancer with unknown primary tumor Plasmacytoma Acute myeloid leukemia Acute lymphocytic leukemia Myelodysplastic disorder, Myeloproliferative tumor Malignant lymphoma Gene (must be included in NGS panel) PRPF31, RHO, RP1, RP2, USH2A, PRPH2, RPGR GJB2, POU3F4, SLC26A4, TECTA GJB1, MFN2, MPZ, PMP22 * RNA fusion gene test: Only Acute myeloid leukemia - ABL1, BCR, CBFB, ETV6, KMT2A, PML, RARA - Specimens should be determined using a validated test method performed by Ministry of Health and Welfare (Korea) validated laboratory - For hereditary genetic testing, only supported once/per disease - For non-hereditary genetic testing, only supported once/per disease, but, in case of recurrence, one addition will be accepted. None HER2, EGFR, ALK, KRAS, NRAS, BRAF, BRCA1, BRCA2, KIT, PDGFRA, IDH1, IDH2, MYC(C-myc), N-myc(MYCN) NRAS, KRAS, TP53 CEBPA, FLT2, JAK2, KIT, NPM1, RUNX1, TP53, IDH1, IDH2 TP53, RB1, JAK2, NRAS, IKZF1 ASXL1, CALR, CSF3R, DNMT3A, JAK2, MPL, RUNX1, SETBP1, SF3B1, SRSF2, TET2 MYD88, BRAF, TP53

NGS for Insurance beneficiaries with diseases (in Korea) Applying for Clinical laboratory for NGS test (Insurance coverage) Main management agencies Ministry of Health and Welfare Reagent/Panel Hardware (H/W) Analysis Software (S/W) RUO (IVD is not necessary) MFDS* approved Dx If.. RUO? -> Clinical laboratory RUO devices approved by MFDS* for NGS testing are permitted. RUO (IVD is not necessary) * MFDS : Ministry of Foodand Drug Safety, Korea

NGS for Medicare beneficiaries with advanced cancer Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N) 1. Patient has: 1 either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer 2 either not been previously tested using the same NGS test for the same primary diagnosis of cancer or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician 3 decided to seek further cancer treatment (e.g., therapeutic chemotherapy) 2. The diagnostic laboratory test using NGS must have: 1 FDA approval or clearance as a companion in vitro diagnostic 2 an FDA approved or cleared indication for use in that patient s cancer 3 results provided to the treating physician for management of the patient using a report template to specify treatment options. 54

NGS based test and Medicare coverage CMS has proposed three pathways through which NGS cancer panels may garner Medicare coverage. - The agency said it will grant full coverage for genetic markers on the panel that have premarket approval (PMA) from the FDA as a companion diagnostic where testing is required for the safe and effective use of a drug. - For markers without CDx status, but that the FDA has cleared or approved for use in a patient's treatment plan with other information (such as MSKCC 468-gene oncopanel MSKIMPACT), CMS is willing to grant coverage with evidence development (CED), when the lab collects patient outcomes in a prospective registry. - For lab-developed tests without the FDA's blessing that are performed in a CLIA-certified lab the majority of tests on the market CMS is proposing CED when tests are included in a National Cancer Institute National Clinical Trial Network study. 55

Companion diagnostic development : News_NGS-CDx FoundationOne CDx (F1CDx), Foundation Medicine

Companion diagnostic development : News_NGS-CDx FDA Grants Breakthrough Device Designation to Foundation Medicine Liquid Biopsy Assay (Apr 26, 2018) FoundationACT is a liquid biopsy assay for solid tumors that analyzes circulating tumor DNA (ctdna) in blood.

Development : News_NGS-IVD MSK-IMPACT, MSK Cancer Center A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. MSK-IMPACT is a single-site assay performed at Memorial Sloan Kettering Cancer Center. Special instrument requirement: Illumina HiSeq 2500 Sequencer (qualified by MSK)

Risk of NGS-based test.. CMS-Proposed Coverage of NGS Cancer Tests Could Lead to Off-Label Scripts, Oncologists Worry (27 th Feb, 2018) CMS: Centers for Medicare & Medicaid Services Solid tumor patient Positive Negative A perspective that hasn't gotten as much attention is that the CMS draft coverage decision is perhaps not restrictive enough, and that the policy could be bad for patients by increasing off-label drug use based on the results of NGS panels. Off-Label prescription (Increase risk of Patient)

Streamlining FDA s Regulatory Oversight of NGS tests The FDA's Role in Advancing Precision Medicine (April. 2018) 1) In April 2018, the FDA issued two final guidances that recommend approaches to streamline the submission and review of data supporting the clinical and analytical validity of NGS-based tests. 2) These recommendations are intended to provide an efficient and flexible regulatory oversight approach: as technology advances, standards can rapidly evolve and be used to set appropriate metrics for fast growing fields such as NGS. 3) Similarly, as clinical evidence improves, new assertions could be supported. 4) This adaptive approach would ultimately foster innovation among test developers and improve patients' access to these new technologies.

5. Suggestion

Suggestion 1. Unfavorable discordance of Biomarker test 2. Increase the Single Lab PMA concept test Global Central Lab 3. Patients and Payers First 4. Companion diagnostics and new drugs should be simultaneously developed and applied for approval. 5. The labels of a drug and its companion diagnostics must specifically indicate their association and effectiveness.

Suggestion Intended use <Companion Diagnostics> Selection of specific drug (ex.tki) target patients Companion diagnostics (CDx) <Complementary Companion Diagnostics> May be associated with enhanced survival from specific drug (ex. TKI) No Complementary CDx Yes Meets the purpose of assay No Yes <In-vitro Diagnostics> Detection and identification of mutations in specific gene Market surveillance Traceability <Laboratory Developed Test> X No Laboratory developed test In-vitro diagnostics Yes Permission of the assay (Off-label only) Meets the purpose of assay Source : 동반진단의가치반영을위한정책개선제안, 의료기기뉴스라인 (2017.06.14) Permission of the assay (Research Use only) 63

Thank you for your attention! 64