Session 2: Regulation of Genetic Testing- view from FDA OHOP Gideon Blumenthal, MD Office of Hematology Oncology Products Center for Drug Evaluation and Research, US FDA

Key Questions (from Dr Mansfield, session chair) Should FDA be encouraging broad NGS tests or keep focusing on panels which are limited to known mutations/genes? What kind of test should FDA be looking for in terms of actionability particularly with regard to hematologic cancers? What is the clinical utility of these tests? What should we do about differences between tests that are supposed to be measuring the same thing? How do we set the parameters? Are there labeling questions that we should be asking (appropriated labeling of drugs and devices) so that physicians know how to use them?

Companion Diagnostics (July 2016) Target Site Drugs Technique Diagnostic Co EGFR mutation NSCLC erlotinib, afatinib, gefitinib, osimertinib RT-PCR Roche, qiagen P53 CLL venetoclax FISH abbott KIT D816V ASM imatinib ARUP PDGFRB MDS/MPD PDL1 pembrolizumab IHC Dako ALK crizotinib FISH, ALK Abbott, ventana KRAS CRC cetuximab, panitumumab BRCA Ovarian olaparib PCR, sanger Myriad EGFR protein C-Kit protein GIST HER2 Breast, GEJ trastuzumab, pertuzumab, ado-trastuzumab-emtansine IHC, FISH, CISH Dako, Ventana, Abbott, biogenex, Life, Leica BRAF V600 Melanoma vemurafenib, dabrafenib, trametinib, cobimetinib Bio-merieux, roche

Evolving companion diagnostic paradigm Single analyte/single gene/single drug multiplex platform/multiple drugs Tissue only blood + tissue

Oncologist, June 2016 “The primary uncertainty is the lack of an approved companion diagnostic to reliably select patients with tumors that contain the ROS1 alterations… This uncertainty will be mitigated by a postmarketing commitment… to support the availability of an in vitro diagnostic device for the detection of ROS1-positive mNSCLC… Per the guidance for industry, FDA may decide to approve a drug, even if a companion diagnostic device is not yet approved, when the drug is intended to treat a serious or life-threatening condition for which no satisfactory alternative treatment exists and the benefits of the drug are so pronounced as to outweigh the risks from the lack of an approved device.” In vitro companion diagnostic guidance for industry and FDA staff. http://www.fda.gov/downloads/medicaldevices/deviceregulationand gudance/guidancedocuments/ucm262327

Companion diagnostics versus “complementary diagnostics” Companion diagnostic- well established (>22 drug/ co-dx pairs) essential for safe and effective use of a drug Complementary diagnostic- draft guidance pending Useful to identify patients more/less likely to derive benefit from a drug? PD-L1- nivolumab (NSCLC, melanoma) PD-L1- atezolizumab (bladder)

Example of pre-post competitive harmonization Drug BMS Merck GTECH Medi/AZ Diagnostic Dako Ventana Cell Type Tumor Tumor or Immune Cell Cut-offs >1%,>5% >1%,>50% IHC 0-3 >25% clone 28-8 22C3 SP142 SP263 FDA-AACR-ASCO Public Workshop Complexities in Personalized Medicine: Harmonizing Companion Diagnostics Across a Class of Targeted Therapies March 24, 2015, Washington DC IASLC-AACR-Industry PDL1 cross-validation consortium Preliminary data from 37 NSCLC specimens presented at AACR 2016

FDA Public Workshop on NGS-based Oncology Panels: February 2016 Intended use of NGS-based Oncology Panels “X is a qualitative IVD that uses high throughput parallel sequencing technology intended to detect sequence variations using the [instrument name]. The XX is indicated as an aid in characterizing sequence variations in [xx genes] on [DNA and/or RNA] isolated from [YY] specimens. The device is also indicated as a CoDx to aid in selecting oncology patients for treatment with the targeted therapies listed in Table 1 in accordance with approved therapeutic product labeling” Table 1 Gene Variant Status Tissue Type Targeted Therapies Results other than those listed in Table 1 are only indicated for use in patients who have already been considered for all appropriate therapies… safe and effective use has not been established for selecting therapy using this device for the variants in the associated tissue types not listed in Table 1. Analytical performance has been established for the variants in table 2. Table 2 Gene Variants Sample Type Tissue Type LoD

Rare variant information in drug labeling: afatinib for EGFRm mNSCLC- example #1

Rare variant information in drug label: ivacaftor for Cystic Fibrosis- example #2

Many genes, even more variants A challenge moving forward: PARP inhibitors for DNA repair defects in mCRPC (as an example) Many genes, even more variants What if spectrum of genes/variants not captured in the pivotal studies? Mateo J, Carreira S, Sandhu S et al. NEJM Oct 29, 2015

Key Questions Should FDA be encouraging broad NGS tests or keep focusing on panels which are limited to known mutations/genes? What kind of test should FDA be looking for in terms of actionability particularly with regard to hematologic cancers? What is the clinical utility of these tests? What should we do about differences between tests that are supposed to be measuring the same thing? How do we set the parameters? Are there labeling questions that we should be asking (appropriate labeling of drugs and devices) so that physicians know how to use them?

Recommendations Concordance across platforms Consider tiered levels of evidence to determine actionability of rare variants in product labeling Consider establishing in-house expertise and external advisors to interpret diverse pipelines of data (non-clinical, registry, EMR, clinical trial) on actionability