International SAE Consortium Ltd An International Industrial Biomedical

International SAE Consortium, Ltd An International Industrial Biomedical Consortium Researching the Genetic Basis of Drug Related Serious Adverse Events “The i. SAEC’s Research into the Genetics of Severe Adverse Events via EHRs Supported Collaborations” UK PGx & Stratified Medicines Meeting 28 September, 2011 1

Topics § i. SAEC Overview & Status § EHR Pilots – Overview and Current Status § Issues and Opportunities Associated with EHR based research § Discussion Qualifier: We are at a fairly early stage in organizing and executing these EHR pilots … more definitive insights will be forthcoming in the future. 2

i. SAEC Update 3

i. SAEC’s Website http: //www. saeconsortium. org 4

i. SAEC’s Mission “The i. SAEC will identify DNA-variants useful in predicting the risk of drug induced serious adverse events. ” 5

i. SAEC – Scientific Focus/Core Goals § Supporting the development of existing and new international networks to obtain well phenotyped cases and controls for PGx research on important drug-induced SAEs § Developing effective whole genome genotyping and sequencing methods for SAE research § Supporting the development of the computational methods necessary for effective GWAS analysis (both genotyping and sequencing) § Creating a timely and publicly available scientific “databank”(raw data and genetic markers) associated with key drug-induced SAEs § Managing the intellectual property related to genetic markers associated with SAEs, to ensure broad and open access to all users in all settings 6

Our Origins & Rationale § Origins: • • • FDA and industry biomedical collaboration consortium model Private 501 c 3 entity formed to do research in the public good 2006 -07 -- Formation 2007 -2009 – Phase 1 2010 -2013 – Phase 2 (underway) § Rationale: 1. 2. 3. 4. Scale/Pooled risk Improved pace of the science > research productivity Global orientation to cover ethnic diversity Public health need 7

i. SAEC Phase 1 Operational Perspective Core Investments SSR GWAS, Paper & DRs Phase 1 Execution § DACC development § SJS initial GWAS (pilot) § DILI network expansion § DILI GWAS characterization & analysis § Data release[s] § Phase 2 planning 2007 -09 Dividend s! Td. P GWAS, Paper (1) & DR SAE GWAS Cohorts Member (3) DILI GWAS, Papers (3) & DRs (3) DILI & Agranulocytosis Sequencing Pilots EHR SAE Case Sourcing Pilots (2) 8

i. SAEC’s Phase 1 Membership/Collaborators Members/Directors Spanish DILI EUDRAGENE DILI & SSRs External Collaborators/Contributors 9

i. SAEC Phase 2 Research Objectives (2010 -2013) Enhanced Efforts 1. Further characterize the genetics of “drug induced immunologic SAEs” (SSR, AHSS, & DILI) associated with specific drugs and ethnicities 2. Pilot novel, international EHR supported research channels (HMORN, EHR vendors partnerships, etc. ) vital to drug-specific SAE research. Continuing Efforts § Develop improved genotyping and sequencing approaches for SAE genetics research § Develop a publicly available database of PGx markers associated with key SAEs/across drugs § Manage IP relating to PGx markers useful in predicting SAEs to ensure broad and open access Caveat … § Maintain a primary focus on understanding immunologically influenced SAEs (AHSS, DILI, & SSR). . . but be opportunistic where prudent 10

i. SAEC Phase 2 Membership (2010 -13) Drug induced immunologic SAEs In-kind Members Regulatory Participants 11

Pathways to More Focused SAE Case Cohorts Genetic Markers Discovery &Validation Academic Networks Pharmaco Safety Cohorts IHS research (via EHRs) v IDILIC v ITCH v Chinese SAENet v ITB Network (Mc. Gill Univ. ) v Peds Network v Global, Cross Industry v Key SAEs Existing & New v HMO Research Network (HMORN) v European Mkts (Finland pilot) “Efforts to increase the odds of meeting Phase 2 Rx and ethnic diversity goals, while piloting new EHR research channels” LS EHR Provider databases v SAEC (Cerner) Phase 2 Pilot Project US based large hospital network (SAENet) v CHI/SAENet v Medco pilot i. SAEC Phase 2 Case Ascertainment Pilots Scalability & Specificity of Safety PGx Research 12

Phase 2 – Phenotype & Technology Focus • DILI (expansion) • SSR (expansion) • AHSS (new) EHR Identification & Enrollment From HMOs, IHNs & EMR Vendors Web-based Enrollment via Discovere platform Phenotype Standardization Program Phase 1 Develop draft phenotypic definitions DILI, DISI & Di. Td. P Phase 2 Formation of Expert Working Groups/ development of final definitions Phase 3 PSP Consensus Conference/Publicatio n of recommendations CP & T 13

International DILI Consortium (i. DILIC) Phase 2 Enhanced Academic Network Web Based Clinical Network Canadian Network EUDRAGENE & Cerner 2 b Other EMR Vendors IDILI Clin. Investigator Network SAEC Members /Pharmacos Int. TB Study /Pharmacos Menzies et al (Montreal) Expression Analysis & Seq. Partnerships Spanish DILI Network Ann Daly & Guru Aithal Newcastle Coordinating Hub 500+ Cases SAEC Genomics Core DILIN NIDDK SAEC DACC Columbia University & Select Analysis Partnerships Japanese NIHR HMORN DNA Repository PGx Net Newcastle

IDILIC Phase 2 Collection Target Rx 2012 Forecast -- PTD (as of 9/11) SAE Effect Sample Size (Minimum Estimate) Ethnicity Focus Estimated GWAS Start Date Augmentin DILI 100 (164) Yes All (HMORN & Chinese) Q 4 2012 Carbamazepine DILI 50 (7) No All (HMORN & Chinese) Q 4 2012 Diclofenac (Select other NSAIDs) DILI 50 (66) Yes All (HMORN & Chinese) Q 4 2012 Isoniazid/ anti-TB agents DILI 50 (134) Caucasian/Asian Q 3 2012 (with Chinese SAENet & Intern TB Therapy Consortium) Azathioprine/6 mercaptopurine DILI 50 (55) Caucasian Q 4 2012 Others/Statins DILI 50 Caucasian Q 4 2012 Drug Yes Yes 563 cases PTD 15

International Consortium on Hypersensitivity (ITCH) Phase 2 Enhanced Academic Network SAEC Genomics Core Web Based Clinical Network ITCH Network Pirmohamed et al 500+ Cases & Canadian Network SAEC Members /Pharmacos Expression Analysis & Seq. Partnerships European PGx Network HSS Investigator Network [6] – Spielberg (US), Shear (Canada), Day, Shiohara (Japan) etc SSR Investigator Network [5] – GATC, Italy, & Singapore Eudragen e SAEC DACC Cerner 2 b Other EMR Vendors Columbia & Select Analysis Partnerships HMORN DNA Repository Liverpool

ITCH Phase 2 Collection Target Rx 2012 Forecast -- PTD (9/11) SAE Effect Sample Size (Minimum Estimate) Ethnicity Focus Estimated GWAS Start Date Carbamazepine (Other antiepileptic drugs) DILI/AHSS ~50 (75) Yes All (HMORN & Chinese) Q 4 2012 (Note: Munir’s 3/11 NEJM CBZ GWAS paper) Allopurinol AHSS/SSR 50 No Caucasian 2012 Beta-lactam antibiotics AHSS/SSR 50 (50) Yes Caucasian late 2011 Amoxicillan & Clavulanic AHSS/SSR 100 (237) Yes Caucasian 2012 NSAIDS (Acetic Acid & Others) AHSS 50 ? ? Caucasian 2012 Sulphasalazine/ Sulfamethoxazole/ other Sulfonamides AHSS/SSR 50 (39) Yes Caucasian 2012 Nevirapine AHSS/SSR 100 (109) African 2010/2012 Drug Yes 436 cases PTD 17

Shanghai Jiao Tong University Bio-X Institute 　　 Honorary director of Bio-X Prof. Steve Zhu Nobel Prize Laureate Director of Bio-X Prof. Lin He, Ph. D Member of Chinese Academy of Sciences President of Chinese Society of Medical Genetics

Chinese SAENet case collection network 16 9 17 4 13 27 20 23 14 5 82 12 29 34 19 25 3 32 21 33 26 28 10 24 22 11 18 30 1. Large clinical network (25) covering all provinces in China 2. Larger hospitals (PLA) have EHRs 15 1 31 Bio-X Institutes 6 7

Chinese SAENet Network Development Status § Current DILI Cases: 30 (multiple Rxs) § Current SJS Cases: 16 (Carbamazepine): § Current Participating Hospitals (8): § Hospitals currently under development (7): 20

EHR Pilots – Overview and Current Status 21

Why i. SAEC’s EHR Pilots? § Expand channels to identify/recruit more SAE/ADR cases (Scale) § Need for more specific phenotype/ethnicity/drug mix (Diversity) § More insight into potential yields before case recruitment (Efficiency) § Pace of case identification/ascertainment (Speed) § Insight into EHR opportunities and issues (operational, data quality, privacy, IC, and networking issues) § Better understand how to collaborate across the various EHR players, in light of different objectives, skills and capabilities § Build LT strategic (PGx) research capabilities i. SAEC 22

EHR Pilots Current Stage of Development HMORN SAENet Finland CHI Informatics Piloting § DILI & SSR (Hispanic bias) § EWGAP 2 (Caucasians) § DILI (All) § SSR (All) § AHSS (All) § DILI (Caucasians) § SSR (Caucasians) § AHSS (Caucasians) § DILI (All) § SSR (All) § AHSS (All) Clinical Collab. Org. /Planning Clinical Collab. Execution Review & Evaluation Stage of EHR Research Pilot Medco Pediatric Network 23

HMO Research Network § 16 HMOs § 20+ million patients § Strong outcomes/ translational research focus § Genetics research core § Common clinical data warehouse linked to EHRs

Phase 2 – HMORN Study Status & Timing § 1 st Genetic Study Ever Carried Out Across the HMORN Ground breaking effort § IRB approved & contract signed at 7 sites; pending at 2 § Creating SOPs for specimen collection, handling, transfer (In conjunction with Expression Analysis) § Creating group Data Use Agreements between all sites & adjudicators (under prep) § Deliverables/Timing: • • • Launch of recruitment at majority of sites (Oct. 2011) Estimated recruitment midpoint (Mar. 2012) Estimated recruitment completion (September, 2012) Samples to sample repository in quarterly traunches (Q 2 -3`12) Final Study Data Transfer (Nov. -Dec. 2012)

Project SAENet SAEC Genomics Core Expression Analysis & Seq. Partnerships i. SAEC & ITCH/IDILIC Hubs & SAEC DACC Columbia, Sanger & Select Analysis Partnerships Cerner. Millennium® SAEC Members /Pharmacos

SAENet – Key Milestones § Q`4 `10 • Formed join project management team (4) (Arthur Holden & Julian Arbuckle from i. SAEC) • Draft operating plan • CHC -- initiative launch • Marketing/study materials preparation § Q 1`11 -Q 4`11 • Large hospital solicitation and contracting • IRB approvals § Q 1`12 -Q 4`12 • Case identification & enrollment via ITCH and IDILIC Clinical Coordinating Centers § Q 1`13 • Program assessment & planning for expanded safety network (if prudent). 27

§ § NHGRI-funded national consortium formed to develop, disseminate and apply approaches to research that combine DNA repositories with electronic medical record systems for large-scale high-throughput genetic research Network institutions • • § § Group Health/University of Washington Marshfield Clinic Mayo Clinic Northwestern University Vanderbilt University Geisinger Health Mt. Sinai School of Medicine Consortium also includes a focus on social and ethical issues such as privacy, confidentiality, return of genetic research results, and the interactions with the broader community Nearly 50, 000 samples with Genome-wide SNP genotyping http: //www. gwas. net

e. MERGE consortium results (Phase 1) § EHR-based phenotypes can advance genomics research (Kho et al. Sci. Transl. Med. 2011, April 20, 3; 79: 79 re 1) § Replication of T 2 D, cataract, and several other genetic variants associated with complex disease. § Identification of genetic variants associated with hypothyroidism without new genotyping (Denny et al. Am. J Hum. Genetic, in press) § Complement Receptor 1 Gene Variants are Associated with Erythrocyte Sedimentation Rate. Kullo et al. 2001. Am. J. Hum. Gen. 89, 1.

Issues Associated EHR Based Research 30

Early Report on our Issues/Challenges § New research collaborations always take more time! § Genetics research, leveraging EHR data, is new (groundbreaking) for most of the HMOs/private tertiary hospitals § Limited experience EHR identification and adjudication activities (vs traditional academic networks) § PSP outputs have been essential, but we need > sharing/ publication of “data mining algorithms/approaches” … other phenotypes beyond DILI/SSR/AHSS § Degree of clinical/other data integration across providers (different platforms, ontologies, data structures, etc) § IC variability affecting data release impact 31

Strategic Discussion Points : EHR Supported Genetic Research § How can we better enhance scale and collaboration across potentially large networks? (e. g. , US-EHR vendor consortium, HMORN, IMI initiative(s) and Emerge) § How can we enhance “global” studies (across platforms, cultures, and languages)? § When and how to best involve the (global) regulators? § Need to increase publications and sharing of “data mining algorithms/ approaches. 32

i. SAEC/Pharmaco Sponsored EHR PGx. Net SAEC Genomics Cores Expression Analysis & Seq. Partnerships i. PGx. C (Non-Profit CRO) and PGx Data Center & SAEC DACC Columbia, Sanger & Select Analysis Partnerships SAEC Members /Pharmacos

i. SAEC Facilitated PGx Networks (Phase 3) 34

EHR supported PGx research …. … New day filled with promise, opportunities & challenges 35