1. Informatics in Breast Cancer Research I-SPY 2 TRIAL & TRANSCEND Sarah Davis, MS University of California, San Francisco December 6, 2011

2. I-SPY 2 TRIAL Five Critical Components Neoadjuvant Setting Molecular and Imaging Biomarker Guidance Multiple Drugs Tested Simultaneously Adaptive Trial Design Common Platform for Sharing Data

3. I-SPY 2 TRIAL Screen phase 2 agents in combination with standard chemotherapy in neoadjuvant setting –Endpoint is pCR –Intermediate endpoint is MRI Volume Accelerate process of identifying drugs that are effective for specific breast cancer subtypes –Integration of biomarkers Reduce the cost, time, and number of patients needed to get effective drugs to market –“threshold” is 85% predicted likelihood of success in a 300-patient phase 3 trial for drug-biomarker pair Design goals of I-SPY 2

4. I-SPY 2 TRIAL SURGERYSURGERY *HER2 positive participants will also receive Trastuzumab. An investigational agent may be used instead of Trastuzumab. Tissue Paclitaxel* + Investigational Agent C AC MRI Biopsy Blood Draw MRI Blood Draw MRI Blood Draw Paclitaxel* + Investigational Agent D AC Paclitaxel* + Investigational Agent E AC Paclitaxel* + Investigational Agent B AC Paclitaxel* + Investigational Agent A AC Paclitaxel* AC ONSTUDYONSTUDY MRI Biopsy Blood Draw MUGA/ECHO CT/PET Screening RANDOMIZERANDOMIZE Consent #2 Treatment Consent Consent #1 I-SPY 2 Adaptive Trial Design

5. I-SPY 2 TRIAL SURGERYSURGERY Tissue Paclitaxel* + Investigational Agent C AC MRI Biopsy Blood Draw MRI Blood Draw MRI Blood Draw *HER2 positive participants will also receive Trastuzumab. An investigational agent may be used instead of Trastuzumab. Paclitaxel* + Investigational Agent D AC Paclitaxel* + Investigational Agent E AC Paclitaxel* + Investigational Agent B AC Paclitaxel* + Investigational Agent A AC Paclitaxel* AC ONSTUDYONSTUDY MRI Biopsy Blood Draw MUGA/ECHO CT/PET Screening RANDOMIZERANDOMIZE Consent #2 Treatment Consent Consent #1 I-SPY 2 Adaptive Trial Design (con’t)

6. I-SPY 2 TRIAL SURGERYSURGERY Tissue Paclitaxel* + Investigational Agent C AC MRI Biopsy Blood Draw MRI Blood Draw MRI Blood Draw *HER2 positive participants will also receive Trastuzumab. An investigational agent may be used instead of Trastuzumab. Paclitaxel* + Investigational Agent D AC Paclitaxel* + Investigational Agent E AC Paclitaxel* + Investigational Agent B AC Paclitaxel* + Investigational Agent A AC Paclitaxel* AC ONSTUDYONSTUDY MRI Biopsy Blood Draw MUGA/ECHO CT/PET Screening RANDOMIZERANDOMIZE Consent #2 Treatment Consent Consent #1 Paclitaxel* + Investigational Agent FG AC I-SPY 2 Adaptive Trial Design (con’t 2)

7. I-SPY 2 TRIAL I-SPY 2 Adaptive Trial Schema: Screening & Randomization Patient presents with newly diagnosed ≥ 2.5cm invasive tumor consents to be Screened Core biopsy to assess eligibility Eligibility determined by:  Ability to tolerate MRI  Ability to generate 44k Agilent microarray  Other clinical variables Patient not on study Not considered good candidate for chemotherapy Patient not on study Not considered good candidate for chemotherapy Patient On Study Randomized to treatment arm based on:  ER, PR status  HER2 Status  MammaPrint score Patient On Study Randomized to treatment arm based on:  ER, PR status  HER2 Status  MammaPrint score Is patient: MammaPrint Low Risk ER + and HER2 - Is patient: MammaPrint Low Risk ER + and HER2 - Yes No

8. I-SPY 2 TRIAL How biomarkers are used in I-SPY 2 Qualifying Biomarkers  RPMA Pathway Markers  Drug Sensitivity Predictor  RCB Predictor (Affy Array) .... Used to Validate Response to Therapy, done in CLIA Lab Exploratory Biomarkers Reflects Next Generation Technology (keeping pace)  DNA Methylation  Exon Sequencing  RNA Sequencing  miRNA  Circulating Tumor Cells  Pharmacogenomics  MRI SER Segmentation .... Stratification Biomarkers Used for Stratification, Response to Therapy (may require IDE)  ER, PR, HER2 (Community)  MammaPrint (Agilent array)  TargetPrint (Agilent array)  MRI Volume (Sentinelle)

9. I-SPY 2 TRIAL Biospecimen Processing in I-SPY 2 Biospecimen Collected Biospecimens Processed  Tissue sectioned, tumor cellularity assessed  Tissue processed (per SOP)  Samples aliquoted, stored (per SOP) Ship to I-SPY Lab Assays Performed, Results Obtained (Stratification, Qualifying, Exploratory) Ship to Research Labs (per Protocol) caIntegrator Tolven eCHR (Case Report Form) Assays Results Reported Stratifying Qualifying, Exploratory

10. I-SPY 2 TRIAL Informatics Needs of I-SPY 2 Manage information across multiple sites Data gathering must be closely monitored as the trial depends on rapid eligibility determination and therapeutic intervention - do not want to delay therapy Randomization as a web service (automated - but with review) Combining evaluation of drugs and biomarkers together –Biomarker data is of various types (arrays, imaging volume, numeric scales, etc..) Scientists need access to data early and in an integrated fashion (one stop shopping)

11. I-SPY 2 TRIAL What is TRANSCEND? TRANslational Informatics System to Coordinate Emerging Biomarkers, Novel Agents, and Clinical Data An IT Bundle to Support Adaptive Trials with Novel Agents and Emerging Biomarkers

12. I-SPY 2 TRIAL TRANSCEND Objectives Develop an information management infrastructure to support adaptive clinical trials like I-SPY 2 Provide real-time data verification for more efficient analysis of trial data Provide a demonstration of caBIG  infrastructure in use in a large multi-center trial Demonstrate integration of a clinical system (electronic health record system) with a clinical research infrastructure

13. I-SPY 2 TRIAL Physician Reported Data A large fraction of clinically produced data in EHRs is ‘narrative’ text and not computable EHRs typically focus on ‘primary use’ of data, so narrative text is fine for this – provisioning clinical processes and care “Secondary Use” –Eg: Prospective/Retrospective research, Quality Improvement, Comparative effectiveness –Typically requires analytics, which require structured, high- quality, “controlled” data

14. I-SPY 2 TRIAL What is new or different about TRANSCEND? Using a clinical information system rather than Clinical Trials Management System to collect patient data through CRFs Everything is web accessible without the need of downloadable plug-ins Randomization is adaptive, functions via web service Integration of caTISSUE with a clinical information system in the context of a trial Using caINTEGRATOR v2.0 as a scientist portal to study data –caARRAY for storing data that is accessible via caINTEGRATOR

15. I-SPY 2 TRIAL Tolven eCHR Data Coordinating Center Study Sites Case Report Forms Study Sites Case Report Forms Agendia  Integration Hub (caXchange) Integration Hub (caXchange) caTissue Suite caIntegrator caAers caArray Research Labs MD Anderson Randomization Engine Automated interface Manual interface TRANSCEND - Systems Overview

16. I-SPY 2 TRIAL TRANSCEND Interoperability Standards for Data Exchange Open-source HL-7 RIM (eCHR) Semantic Interoperability modeled on BRIDG 2.1 –Use of caDSR Common Data Elements Systems for Data Exchange caExchange iHUB-Mirth Connect (Enterprise Service Bus)

17. I-SPY 2 TRIAL Implementation and Use of TRANSCEND in an Adaptive Clinical Trial Web-based and very easy to use for the end- user –Study Coordinators, Monitors, and Investigators Auto-population of data across systems reduces manual data entry errors –Specimen IDs in caTissue Real time data collection & review reduces delays in getting trial data to Data Review Committees and Trial Investigators

18. I-SPY 2 TRIAL Electronic copy of source documentation with each CRF Easy to complete case report forms with smart logic TRANSCEND – eCHR Data Collection

19. I-SPY 2 TRIAL Real-time data review and verification Instant submission of CRF with source documentation to Data Coordination Center TRANSCEND – eCHR Data Verification

20. I-SPY 2 TRIAL TRANSCEND – eCHR Data Collection (con’t) Email alerts to when a CRF is ready for review & verification Email alerts when a CRF is rejected by the DCC

21. I-SPY 2 TRIAL TRANSCEND – eCHR Data Collection

22. I-SPY 2 TRIAL What Were the Challenges for End-Users? Change in Clinical Research Culture –Real time data collection & verification Study Coordinators: Cannot wait weeks to complete a case report form Need case report forms to be verified before patient can proceed in trial Make source data available electronically and de-identified Trial Monitors: Cannot wait weeks/months to review case report forms for data entry accuracy Challenges normal way of business – drastically reduce time spent on-site at each study site Identified gaps in standards of verifying data –Trial Monitors are also playing the role of Data Auditor

23. I-SPY 2 TRIAL What Were the Challenges Technically? Overall –Move towards ‘enterprise bus’ as an integration rather than API-based point-to-point integration –Install systems early to deal with logistical issues far in advance of needing the systems caExchange –Required custom Java programming –Transaction rollback not an option However iHub has this capability caTissue –Transaction rollback not an option Requires manual removal of an entry

24. I-SPY 2 TRIAL Future Direction with 2TRANSCEND Integrate additional platforms Web-based Patient Communication and Care Plan –Aids in decision making about participating in a clinical trial as well as enabling study staff to communicate with patient’s regarding study appointments Web interface allowing patients to directly input: –Adherence to treatment regimens –Adverse events (PRO-CTCAE) –Follow-up information Adopt Annotation Imaging Mark-up (AIM) tool to enable researches ability to centrally review and analyze images

25. I-SPY 2 TRIAL How to Achieve TRANSCEND Functionality with Other Systems TRANSCEND-like interoperability with other systems in support of clinical trials & biobanking OpenClinica Local Institutional CTMSs Cooperative Group Trial Management Systems ? Others ??

26. I-SPY 2 TRIAL Dr. Laura Esserman – I-SPY TRIAL, TRANSCEND PI (UCSF) Dr. Michael Hogarth - TRANSCEND Technical Director (UC Davis) Meg Young – TRANSCEND Project Manager (UCSF) Sarah Davis – I-SPY 2 TRIAL Manager (UCSF) –Joyce Lee, Julia Lyandres (software testing, quality control) Sorena Nadaf – Informatics Design (UCSF) Dr. Angela DeMichele – Clinical Oncology (UPenn) Don Berry & Kyle Wathen – Randomization Engine (MDACC) John Churin – Software Lead Engineer (Tolven) Ashwin Koleth – Software Development (Cyrus-XP) John Koisch – Architecture (NCI) Kathy Hajopoulos – Project Oversight (UCSF) Nancy Roche – Project Oversight (SAIC) TRANSCEND TEAM TRANSCEND development funded by the National Cancer Institute (NCI), Subcontract # 28XS197

27. I-SPY 2 TRIAL Dr. Laura Esserman – I-SPY TRIAL, 2TRANSCEND PI (UCSF) Dr. Michael Hogarth - 2TRANSCEND Technical Director (UC Davis) Sarah Davis– 2TRANSCEND Project Manager (UCSF) Meredith Buxton – I-SPY 2 Program Director (UCSF) Dr. Angela DeMichele – Clinical Oncology (UPenn) Don Berry & Kyle Wathen – Randomization Engine (MDACC) John Churin – Software Lead Engineer (Tolven) Ashwin Koleth – Software Development (Cyrus-XP) Eve Shalley – Project Manager (NCI) Santosh Joshi & CBIIT caCIS Team (NCI) Ian Fore & CBIIT caTissue Team (NCI) Paul Baumgarnter & CBIIT caAERS Team (NCI) Juli Klemm & CBIIT caArray Team (NCI) Shine Jacob & CBIIT caIntegrator Team (NCI) Robert Shirley & CBIIT Architechture Team (NCI) 2TRANSCEND TEAM 2TRANSCEND development funded by the National Cancer Institute (NCI), Agreement No. 12ST1002

28. I-SPY 2 TRIAL The clearer the requirements, the more likely to get what you intend Involve actual users in user interface design and workflow reviews Screen and report mock-ups are invaluable! Integrating with clinical systems demands an enterprise approach to information exchange (caXchange, HL-7) Move towards ‘enterprise bus’ as an integration rather than API- based point-to-point integration Install systems early to deal with logistical issues far in advance of needing the systems Do not underestimate the number of data elements you might want or need to code Identifying and managing data elements is a significant undertaking TRANSCEND Design Lessons

29. I-SPY 2 TRIAL TRANSCEND Breakout B – End-User Session Detailed Workflow from End-Users Perspective Questions & Feedback from Community

30. I-SPY 2 TRIAL Tolven eCHR Data Coordinating Center Study Sites Case Report Forms Study Sites Case Report Forms Agendia  Integration Hub (caXchange) Integration Hub (caXchange) caTissue Suite caIntegrator caAers caArray Research Labs MD Anderson Randomization Engine Automated interface Manual interface TRANSCEND - Systems Overview

31. I-SPY 2 TRIAL TRANSCEND & caTissue - Workflow Tolven eCHR Data Coordinating Center Study Sites Case Report Forms Study Sites Case Report Forms Agendia  Integration Hub (caXchange) Integration Hub (caXchange) caTissue Suite Automated interface Manual interface

32. I-SPY 2 TRIAL TRANSCEND & caTissue – Workflow (con’t) Study Coordinator (CRA) - In Clinic - In Tolven Lab Staff - In caTissue

33. I-SPY 2 TRIAL TRANSCEND & caTissue – Workflow (con’t 2) Study Coordinator (CRA) - In Clinic - In Tolven Lab Staff - In caTissue

34. I-SPY 2 TRIAL TRANSCEND & caTissue – Workflow (con’t 3) Study Coordinator (CRA) - In Clinic - In Tolven Lab Staff - In caTissue

35. I-SPY 2 TRIAL TRANSCEND & caTissue – Workflow (con’t 4)

36. I-SPY 2 TRIAL TRANSCEND & caTissue – Workflow (con’t 5)

37. I-SPY 2 TRIAL Implementation of caTissue in the Lab Set up of Lab workflows and caTissue –Setting up actual freezer and mapping –Printing of Labels from caTissue –Setting up child-specimen in caTissue Lessons learned –Engage Lab users in how caTissue works/capabilities Helps with setting up workflows/collection protocols

38. I-SPY 2 TRIAL Questions & Feedback Can other Institutions/Groups extend interoperability of caTissue as used in TRANSCEND? What other systems would you integrate with caTissue?

39. I-SPY 2 TRIAL Questions & Feedback (con’t) Differences in biobanking for adaptive clinical trials vs. traditional? What standards are used in clinical research? –Does this pose any challenges?

40. I-SPY 2 TRIAL Questions & Feedback (con’t 2) How to engage participation from End- Users in design/set-up?

41. I-SPY 2 TRIAL Questions & Feedback (con’t 3) How would you go about setting up IT systems to support your projects/workflow? –What would be the architecture? –Who would be the user of each system?