American Association For Cancer Research American Society .

Supported by:American Association for Cancer ResearchAmerican Society of Clinical OncologySusan G. Komen

Panelists Gideon Blumenthal, MD; US FDA Amy Abernethy, MD, PhD; Flatiron Health Lisa LaVange, PhD; FDA Jane Perlmutter, PhD; Gemini Group Michael Taylor, PharmD, PhD; Genentech3

Friends of Cancer ResearchAnnual meetingNovember 16, 2016

What is RWD/RWE?Real WorldData (RWD)Electronic Health Record(EHR) clinical dataPatient registriesSurveysPragmatic trialsAdministrativeclaims/billingMobile health(smartphones,wearables, social media)Real World Evidence (RWE)“Data generated for purposes other than evidencegeneration from a traditional clinical trial”6

Why RWE/RWD? U.S. adult cancer clinical trials relativelyhomogenous, expensive, (s)low accrual,administrative burdens Questions regarding generalizability once thedrug enters the clinic New technologies may enable the collectionand curation of diverse pipelines of data toenhance learning lifecycle of a therapy7

Potential uses for RWD/RWE in oncology www.fda.govLabeling expansion for efficacy (rare tumor types)Real world dosage and administrationPost-marketing safetyAssessment of REMSUse in patients excluded from pivotal trials (e.g. autoimmune diseasewith immune checkpoint inhibitors)Assessment of special populations (hepatic/renal impairment, brainmets, leptomeningeal mets, elderly)Patient-reported toxicity/efficacy/functionPrognosis in rare genomic subtypesBiomarker prediction (e.g. ORR and DoR based on “liquid biopsy”results versus tissue)Drug utilization8

Potential issues Missing dataData curation (structured vs unstructured)Cohort selectionInformed Consent/ HIPAAQuality Assurance9

Potential Use-Cases discussed in WG Observational post-marketing data in rarecancers Observational follow up of post-progressioncross-over cohort in a randomized controlledtrial Pragmatic randomized controlled trial exploring2 different dosing strategies10

The panel Presentations:– Michael Taylor (Genentech)– Amy Abernathy (Flatiron) Reaction: Lisa Lavange (FDA), Jane Perlmutter (patient advocate) Panel discussion/ Q&A11

Genentech

RWE to Support Regulatory DecisionsUse cases and considerationsMichael D. Taylor, PharmD, PhDDeputy Global Head of OncologyReal World Data ScienceGenentech, A Member of the Roche Group

RWE for Regulatory Decisions What?– Safety & Effectiveness– PMC & Label expansion Why?– Opportunity to learn– Expedite clinical development for serious and life-threatening disease– RCT feasibility and appropriateness

RWE Use Cases Prospectively designed observational study Randomized Phase 2 plus observational study Pragmatic trial

Observational StudyProspectively designedPhase 1b:Treatment AEarlyoutcomesLong-termoutcomesTimeObservational Study:1) Treatment A&2) SOCEarlyoutcomesLong-termoutcomes

Observational StudyProspectively designed Considerations– Study outcomes– Selection bias and confounding– Patient identification– Sample size

Randomized Phase 2 StudyPlus observational studyEarlyoutcomesTreatment A Physician’s Choiceor SOC Physician’s Choiceor SOC Long-termoutcomes RObsTreatment A

Randomized Phase 2 StudyPlus observational study Study Design & Methodological Issues– Trial setting vs observational setting– Sample size Potential for accelerated approval on randomized Ph2 andconversion with long term observational data

Pragmatic TrialExplore new doseStudy data source:Electronic Health RecordsEarlyoutcomesRLong-termoutcomesTreatment AApproved dose Treatment AAlternate dose

Pragmatic trial Study Design & Methodological Issues– Randomization– Consent

Considerations Data Quality Operational & Logistical Issues– Patient level data submission Auditing of source data HIPPA– Data standardization across EMR systems– Linkage of EMR and claims– Consent

Final Thoughts Opportunity to learn through pilots and dialogue– Test ability of data to answer key questions– Test feasibility – can we identify and overcome operational/logisticalchallenges? Opportunity to help patients while learning

16 November 2016Applications of Oncology Real-WorldEvidenceAmy Abernethy, MD, PhDwww.flatiron.com 2016 Flatiron Health, Inc. Proprietary and confidential.

Advances in clinical data capture are creating new opportunities forreal-world evidenceClinicalPracticeClinical TrialDatasetEHRDATA“RWE”Retrospective Capture withLongitudinal Follow-Up“EHR as EDC”Prospective CaptureRetrospective, but near real timein service of prospective work 2016 Flatiron Health, Inc. Proprietary and confidential.26

Advances in clinical data capture are creating new opportunities forreal-world evidenceClinicalPracticeClinical TrialDatasetEHRDATA“RWE”“EHR as EDC”Retrospective Capture withLongitudinal Follow-UpProspective CaptureRetrospective, but near real timein service of prospective workObservational data onoff label useReal-world follow-up onclinical outcomesPragmatic trial 2016 Flatiron Health, Inc. Proprietary and confidential.27

Observational data to complement trialsCase 1: Use of observational data to examine effectiveness of approved agentsused in the off-label setting 2016 Flatiron Health, Inc. Proprietary and confidential.28

RWE Potential Application:Observational data for off-label use of approved agentsContext BRAF V600 inhibitors are approved in melanoma Data from Phase II basket trial in non-melanoma cancers had a signal of response in non-small cell lung cancer(N 20) Among people with BRAF non-small cell lung cancer, is there differential improved response when a BRAFinhibitor is administered? Because of the difficulty of conducting clinical trials in small population, real-world evidence could potentiallysupplement the clinical trial dataRWE Application RWE database of 25,000 aNSCLC patients allows for identification and investigation of any patient cases with aBRAF V600 mutation, tested as part of routine clinical care Centralized, technology-enabled processing allows for further systematic assessment of outcomes by capturing“real-world” tumor endpoints, based on standardized methodology 2016 Flatiron Health, Inc. Proprietary and confidential.29

RWE Potential Application:Observational data for off-label use of approved agentsPotential selection diagram for BRAF patients in the aNSCLC RWEdatabase, based on current cohort:Confirmed Advanced NSCLCN 27,729History of NGS testingStructured order for aBRAF inhibitorFree-text search forBRAF mutationBRAF V600E mutatedTreated with a BRAFinhibitorNot treated with aBRAF inhibitor 2016 Flatiron Health, Inc. Proprietary and confidential.30

Real-world follow upCase 2: Tracking utilization, effectiveness and safety in the transition from clinicaltrials to real-world care after regulatory approval 2016 Flatiron Health, Inc. Proprietary and confidential.31

RWE Case Study: Tracking outcomes in the transition from clinicaltrials to real-world careContext FDA/Flatiron collaborative project to understand safety and outcomes for immune checkpoint inhibitors in aNSCLCas these treatments are adopted post-approvalRWE Application Because patients continue to receive care, EHR platform and data processing supports longitudinal tracking Allows for “updating the story” with additional information on longer term outcomes - such as time on therapy,safety events and overall survivalNext Steps All cases in Flatiron national dataset through March 31, 2016 Additional phases planned for further investigation based on preliminary findings 2016 Flatiron Health, Inc. Proprietary and confidential.32

2016 Flatiron Health, Inc. Proprietary and confidential.33

Comparison of PD-1 treated patients in Flatiron dataset to 056/NEJMoa1501824.EnglJMed. 2016 Flatiron Health, Inc. Proprietary and confidential.34

Pragmatic TrialCase 3: Conducting a prospective pragmatic trial supported by electronic healthrecord data 2016 Flatiron Health, Inc. Proprietary and confidential.35

RWE Case Study: Use of EHR data to support a pragmatic trialContext Hypothetical example presented in white paper - Revised dosing schedule may be safer and equally efficaciouscompared to that which is approved in the label Salford Lung Study serves as a backdrop COPD; new agent vs usual care; conducted in general practices using EHRsRWE Application Use an EHR-derived dataset to plan the study Define standard of care; test eligibility criteria, seek pragmatism in design Use EHR data to populate the study dataset Use linked EHR data to populate study endpoints Tumor response, mortality 2016 Flatiron Health, Inc. Proprietary and confidential.36

RWD in trial design and feasibilityProtocol design informed by common practicepatternsTime between scansDaysSites selected based on rate of NGS testing inrelevant patient populationsNGS results in target patient populationPatients per site 45 days median Ensured protocol design reflects routineclinical practice Selected sites with the greatest potentiallyeligible patient volume 2016 Flatiron Health, Inc. Proprietary and confidential.37

ClinicalPracticeEHRDATAClinical TrialDataset“EHR toEDC”“RWE”RetrospectivePragmatic trialProspective***Retrospective, butnear real time inservice ofprospective work 2016 Flatiron Health, Inc. Proprietary and confidential.38

Conclusions Evolving portfolio of example studies where EHR-generated RWE can beused in service of regulatory and clinical decision-making Data quality must be characterized and optimized Approaches incorporate the longitudinal nature of clinical care Incorporate rigorous analysis plans and technology tools to support efficientunderstanding of information Rigorous assessment of outcomes is critical 2016 Flatiron Health, Inc. Proprietary and confidential.39

Panelists Gideon Blumenthal, MD; US FDA Amy Abernethy, MD, PhD; Flatiron Health Lisa LaVange, PhD; FDA Jane Perlmutter, PhD; Gemini Group Michael Taylor, PharmD, PhD; Genentech

Supported by:American Association for Cancer ResearchAmerican Society of Clinical OncologySusan G. Komen

Annual meeting November 16, 2016. 6 Electronic Health Record (EHR) clinical data Pragmatic trials . RWE Case Study: Tracking outcomes in the transition from clinical . conducted in general practices using EHRs Context Use an EHR-derived dataset to plan the study Define standard of care; test eligibility criteria, seek pragmatism in design .