Individualizing Patient Care through Precision Medicine: Shaping thePrecision Medicine: Shaping the
Industry’s FutureLaura Esserman MD MBA
Professor of Surgery and RadiologyDirector UCSF Breast Care CenterDirector UCSF Breast Care Center
PI: I SPY TRIALs, ATHENA
AgendaAgenda
P i i M di i• Precision Medicine
• Examples: The I SPY TRIALs and AthenaExamples: The I SPY TRIALs and Athena
• Precision medicine IT requirementsq
• Importance of developing and using common Intraoperable toolsIntraoperable tools
Ushering in the Future of Medicineg
TO ENABLE PRECISION MEDICINE
TAILORING CARE TO BIOLOGY, PATIENT Precision Medicine is the art of . . . .
,PREFERENCE, AND CLINICAL PERFORMANCEPERFORMANCE
Two Similar People Are Not . . .Two Similar People Are Not . . .
VeronicaAge 51, 1 cm tumor Works for Walmart
KimAge 51, 1 cm tumorSelf employed consultantRecently divorced single momWorks for Walmart
BRCA 2 carrierPost menopausalGrade 1 ER+ tumor
Recently divorced, single momPre menopausalGrade 3 triple negative tumorPositive nodes
WE NEED A LEARNING PLATFORMWE NEED A LEARNING PLATFORMThat Uses Data on All Patients as a Routine Care
As of 2015 . . . 56.8 million people participate in some kind ofsome kind of fantasy sport
we need
MoneyballMoneyballfor
Medicine
I‐SPY 2 and I‐SPY 3 TRIALS: Changing the Paradigm for g g gDrug Development in Neoadjuvant Breast Cancer
The Right Drug .The Right Patient. The Right Time. Now.
• 30‐50% of women with breast cancer are still die of their diseasef
• It takes 10‐15 years for new oncology drugs to reach patients
• Many new therapeutic options‐ little chance to rapidly get them to patients
• Access to new investigational drugs d d h i th ld lidepends on where in the world you live
• 70‐90% of Phase 3 trials fail to meet endpoint
The Right Drug .The Right Patient. The Right Time. Now.
endpoint
The cost to bring a new drug to the market is over $2 billionover $2 billion
Absence of innovation in trial design/data ll ti t l t i th ffi icollection tools to improve the efficiency
and decrease the cost of trials
Cancer is a subset of diseases
Blockbuster approach not likely to work
70‐90% of Phase 3 trials fail to meet endpoint
The Right Drug .The Right Patient. The Right Time. Now.
Current path is UN-SUSTAINABLE
Test drugs where they matter most (Early stage)Test drugs where they matter most (Early stage)
Use biomarker and imaging guidance,
Use adaptive designUse adaptive design
Develop IT solutions where form functioncollect data in real time, integrate care & research
CHANGE THE WAYWE TESTLeverage a precompetitive collaboration model
CHANGE THE WAY WE TEST PROMISING NEW DRUGS
W t Ri k f S t i R
• Will not be cured with surgery alone
Women at Risk for Systemic Recurrence
• Order of surgery, systemic therapy has no impact on survival outcomes
• Neoadjuvant approach is an opportunity• Neoadjuvant approach is an opportunity– Downstage tumors, refine local therapy options– Better understand response to therapy, prognosis– Accelerate targeted drug development to improve outcomes in highestAccelerate targeted drug development to improve outcomes in highest
risk women– Particularly relevant as a tool to sort out optimal treatments in the
molecular era
Optimize the Clinical Care Process
The Right Drug .The Right Patient. The Right Time. Now. 13
LESSONS FROM CMLAn historically fatal disease that has been turned into a chronic condition
LESSONS FROM CML
Survival in Accelerated and Blast Phase CML Over TimeCML Over Time
Accelerated Phase Blast Phase
Testing new agents in the metastatic setting may NOT be optimal
4A 5A5A
Kantarjian. Blood 119:1981;2012
Neoadjuvantsetting
EmergingTreatments
High Risk for EarlyEarly
Recurrence
Collaborative InfrastructureStandards for Data Collection
The Right Drug .The Right Patient. The Right Time. Now.
II‐‐SPY 2SPY 2
• I‐SPY 2 is a re‐engineering of the drug development and approval process
• Focus is on using neoadjuvant therapy for those that will get systemic therapywill get systemic therapy
THE GOAL:THE GOAL:‐ Find the right treatments (biology), give them at the right time (save lives)g ( )
‐ Generate more investment in developing tailored treatments for “subsets” of disease
The Right Drug .The Right Patient. The Right Time. Now. 17
I SPY 2 TRIAL SchemaI‐SPY 2 TRIAL Schema
TREATMENT��
AC�Chemo‐therapy�
S�U�R�
��NEW�PATIENT�
SCREENING�Paclitaxel*�(control)�Adap ve�
Randomiza on�
���
�G�E�R�Y�
��NEW�PATIENT�
Paclitaxel*�+�Agent�B�12�weeks� 8‐12�weeks�
Paclitaxel*�+�Agent�A�
�MRI�Blood�Draw�Core�Biopsy�MammaPrint�
MRI�Blood�Draw�Core�Biopsy�
MRI�Blood�Draw�
MRI�Blood�Draw�Tissue�
*with�trastuzumab�for�HER2+�
I‐SPY…The Right Drug, The Right Patient, The Right Time…NOW!
I‐SPY 2 Overview
Controversies The Right Drug .The Right Patient. The Right Time. Now.
I‐SPY 3PLX‐3397
I SPY 2: Designed to Optimize Success of Phase 3 TrialsI SPY 2: Designed to Optimize Success of Phase 3 Trials
Principle SolutionTest agents where they matter most
•Neoadjuvant setting, poor prognosis cancers •Integrate advocates into trial planningg p g
Rapidly learn to tailor agents
•Adaptive Design•Neoadjuvant therapy•Integration of biomarkers, imaging g , g g
Optimize Phase 3 trials •Graduate drugs with predicted probability of success in Phase 3 trials for given biomarker profile
Drive Organizational •Adaptive DesignDrive Organizational Efficiency
•Adaptive Design•Master IND•Test drugs by class, across many companies•Shared cost of profilingShared cost of profiling•Financial support separated from drug supply•Shared IT Infrastructure, caBIG
Use Team Approach •Democratize access to data
September 24, 2015 CONFIDENTIAL: Do not disclose outside the I-SPY 2 Project Team. 19
Use Team Approach Democratize access to data•Share credit and opportunity•Collaborative process for development
d hFRAMEWORK: Integrating Care and Research
Linked trial phases could providecould provide additional efficiency and further
Core
S l
The Right Drug .The Right Patient. The Right Time. Now.
Structural
Alignment
I SPY Milestones• Demonstrated that pCR endpoints work better by subtype (I‐SPY 1)
• Enlisted multiple pharma companies into same trial
I‐SPY Milestones
p p p
• Developed I‐SPY 2 infrastructure• IT systems, real time data collection, to support adaptive learning
• New methods to distribute creditNew methods to distribute credit
• Demonstration of the standing trial concept• multiple arms, single backbone and Master IND
• 8 drugs introduced into the study several in the pipeline• 8 drugs introduced into the study, several in the pipeline
• Successful use of Adaptive Randomization in a platform trial
• Graduation of 3 agents with biomarker signatures• Graduation of 3 agents, with biomarker signatures
• Neratanib (Puma Biotechnology) ( Dec 4, 2013): HER2+ HR‐• Veliparib (AbbVie) (Dec 13, 2013): HER2‐ HR‐ (triple negative)• MK2206: Hormone Negative, Hormone Negative and Her2 positive
The Right Drug .The Right Patient. The Right Time. Now. 21
MK2206: Hormone Negative, Hormone Negative and Her2 positive
• Accelerated Approval guidance issued by FDA
• I‐SPY Phase 1 network and I‐SPY 3 International Registration Trials
Integrating Trial Phases: Changing Work Flow
I SPY Phase I Patient safety trial
Integrating Trial Phases: Changing Work Flow
I‐SPY Phase I
I‐SPY Phase I Patient safety trial
I‐SPY 2 Adaptive design trial‐
I‐SPY 2 (Phase II)
I SPY 2 (Phase II)
Adaptive design trialPatients get treatments that are more likely to benefit
I‐SPY 3
more likely to benefit them
(Phase III) I‐SPY 3(Phase III)
Confirmatory trial
The Right Drug .The Right Patient. The Right Time. Now.
I SPY MOREI‐SPY MORE
Goal:Goal:• Interest in extending the I‐SPY model to other indications• Proliferate the acceleration of drug development and
• Drive integration of research and clinical care• Aid other disease groups to establish their own master trial platformsmaster trial platforms• Utilize I‐SPY “Master Trial” methodology and learnings
The Right Drug .The Right Patient. The Right Time. Now.
learnings
ATHENA BREAST HEALTH NETWORK:OVERVIEW AND UPCOMING WISDOM INITIATIVE
Athena Breast Health Network
•Created to facilitate the rapid integration of
Athena Breast Health Network
Created to facilitate the rapid integration of
research advances into clinical care
•Established network with a large community g y
referral base
• 5 University of California Medical Campuses
• 13 Midwest hospitals (Sanford Health)
•>100 providers and researchers in the fields of
primary care, radiology, pathology, surgery,
medical oncology and radiation oncology
•>85,000 women enrolled to date
Athena’s mission is to save lives by transforming how we deliver care today, learn f g y,
from our patients, create life‐changing science, and improve prevention and p p
treatment options tomorrow.
Athena Strategic Initiativesg
Prevention • Personalized risk assessment as part of screening• Prevention counseling for high risk women
• Risk based screening and preventionScreening and
Diagnosis
• Risk based screening and prevention• Tailored frequency• Fewer false positives• Who is at risk for what type of cancerg • Who is at risk for what type of cancer
Treatment • Tailored interventions based on molecular profiling
Survivorship • Better models of care
5
Athena Breast Health Network: A University California initiated system‐wide demonstration project
PATIENTS AND PATIENTS AND PARTICIPATING SITESPARTICIPATING SITES
DATA INDATA IN KNOWLEDGE OUTKNOWLEDGE OUTElectronic Patient QuestionnairesAutomated Risk AssessmentsRisk Models/Web ServicesMolecular Tests
Personalized Risk ProfilePersonalized Biopsy BenefitPersonalized Breast Cancer Treatment Options
RESEARCH/QUALITY IMPROVEMENTRESEARCH/QUALITY IMPROVEMENT
Disease StagingTreatment DecisionsOutcomes
Options for Risk‐based TrialsConnection to BreastCancerTrials.org
RESEARCH/QUALITY IMPROVEMENTRESEARCH/QUALITY IMPROVEMENTBiomarker DiscoveryBiomarker ValidationBiospecimen RepositoryC ti Eff ti R hComparative Effectiveness ResearchStrategies for Personalized MedicineEvidence‐based Management
Athena Infrastructure GoalAthena Infrastructure Goal
• Framework of data collection analysisFramework of data collection, analysis, feedback, and sharing that will serve as a model of a learning health care systemmodel of a learning health care system.• Integrate research and continuous improvement into the routine process of careinto the routine process of care
• Identify clinical and organization feedback measures for routine reportingeasu es o ou e epo g
29
ATHENA PROCESS TODAY
Athena Personalized Risk Assessment
TriggersSchedules Athena Health
Completedat home or in clinic
Feeds into
Mammogramgg Athena Health
Questionnaire
Athena Risk Calculator
BRCAP
into
GailClaus BRCAPro
Elevated Risk Thresholds
Creates
If at elevated risk
Woman’s doctor
Personalized Risk ProfileAthena Database
Breast ClinicPersonalizing Care for Everyone
Athena Breast l hReferred toIf at elevated risk
Clinical Decision Support
Health Specialist
Consultation
Uses
G ti
and Referrals
Lifestyle changes(weight loss, alcohol reduction)
Genetic counseling
Clinical Interventions
ATHENA WISDOM INITIATIVE:IMPROVING OUR APPROACH TO SCREENING
The Screening Debate in the US?The Screening Debate in the US?
• ACS vs. USPSTF– When to start, when to stop, screening intervals, modality]
• Little guidance around operationalizing risk assessment
Some may be under screened some over screened– Some may be under‐screened, some over‐screened
• Preventive services are not reaching women who gmost need them
• Many women are confused and frustrated34
Women Are Caught in the Middleg
35
And many are choosing not to screen at all…
Breast Cancer Screening: What It Can Be
• Based on advances in:
Breast Cancer Screening: What It Can Be
Based on advances in: – Risk‐assessment
Biology– Biology
• More effective at finding “relevant” cancers
• Integrated with prevention
• More cost‐effective (better health care value)
• Personalized
W I S D O M
Women Informed to Screen Depending On Measures of riskDepending On Measures of risk
WISDOM Study Design: Pragmatic TrialWISDOM Study Design: Pragmatic Trial
EligiblePatients
ConsentConsent
Randomized Cohort Observational CohortRandomized Cohort
Randomize
Observational Cohort
Annual Screening
PersonalizedScreening
Annual Screening
PersonalizedScreening
38
adapts over time
WISDOM StudyRisk‐based
Screening Arm
er
t men
t nt
Athena Health
Mammogram‐breast density
USPSTF
BCSC
Risk ModelRisk
BS Con
sume
Engagemen
t
ortal enrollm
and consen Questionnaire
‐family history, comorbidities, previous
biopsies, age, race/ethnicity
RB E
Po Genomic profiling ‐BRCA, BROCA, SNPs‐saliva collection
No screening until age 50
Biennial Mammogram
Annual Mammogram
Mammogram + MRI
Screening Recommendation Notification and Education
Breast Health Specialist counseling
Screening Recommendation Notification and Education
Who Has Skin in the Game?Who Has Skin in the Game?
PCORI &Donors
Patients
PayorsDonors
Paradigm Shift in Breast Cancer ScreeningCancer Screening
Technology partnersAthena partners
Policymakers & scientific bodies
Athena Network
Together, we can usher in a model that allows us as a community to answer critical health questions
What does a pragmatic trial approach require?
• A multi‐stakeholder model where everyone benefits
What does a pragmatic trial approach require?
y• Agreement on what stakeholders get and give• Up‐front agreement about metrics• Commitment to sharing clinical/scientific data and costs• Agreement to change policy if certain conditions met• An infrastructure enabling rapid adoption based on findings
• Decreased overhead to minimize friction in the system• Decreased overhead to minimize friction in the system• Ability to refine risk model over time (learning)• Implement with fidelity and constant "measure‐vention"Implement with fidelity and constant measure vention (measurement and refinement)
Our Value Proposition
• Our starting bounds Recommendations that are all
Our Value Proposition
within acceptable practice standards
• Larger intended goal Moving beyond current• Larger intended goal Moving beyond current practice to:• Learn who is at risk for what kind of cancer
l h h b• Tailor screening so it has the biggest impact
• Our model is prix fixe = low transaction cost/overheadOur model is prix fixe low transaction cost/overhead• We are serving the public, payors are serving customers
WISDOM Trial Starting RecommendationsWISDOM Trial Starting Recommendations
Screening Recommendation Criteria/ThresholdgNo screening • Women aged 40‐49 with a <1.3% 5‐year risk of
developing breast cancerBiennial mammogram • Women ≥50 years old
• Women with a ≥1.3% 5‐year risk (risk of an average 50 year‐old woman)
Annual mammogram • Women aged 40‐49 with extremely dense breastsg g y
• Women at a ≥1% 5‐year risk of developing ER‐breast cancer based on susceptibility SNPs
Annual mammogram + annual MRI • Women who are BRCA1/2 TP53 PTEN STK11Annual mammogram + annual MRI • Women who are BRCA1/2, TP53, PTEN, STK11, CDH1, ATM, PALB2 or CHEK2 positive
• Women with a ≥6% 5‐year risk (risk of an average BRCA i )BRCA carrier)
• Women with a history of mantle radiation
Emergence of an “Ultralow risk” or d l h h ldIndolent Threshold
STO trial long-term survival by Mammaprint Ultra low -
0.8
0.9
1 Treated arm
0.5
0.6
0.7
0.2
0.3
0.4
0
0.1
0 5 10 15 20
High risk Low risk Ultra-low risk
Esserman, Lindstrom, Yau et al Manuscript in preparation 2015
High risk Low risk Ultra low risk
WISDOM Study Value ChainWISDOM Study Value Chain
WISDOMWISDOM
KnowledgeKnowledge
Learn and ImproveLearn and Improve
Data InformationData Information
45
“One Size Does NOT Fit All”One Size Does NOT Fit All
Population Medicine Precision MedicinePopulation Medicine Precision Medicine
100,000
Tailored screening recommendation for individual woman
Lower Barriers for Each Patient to ParticipateLower Barriers for Each Patient to Participate
FILL THE GAPS IN CURRENT EHRS
Lowering the BarriersLowering the Barriers
• Patient Engagement Platform
• Physician Engagement Platform
• Use patient reported data efficiently over time• Use patient reported data efficiently over time
• Tools to enter data once and use many times
Enter Once, Use Many TimesIdeal Data Source
Patient Reported data Provider Verified Data
History/Baseline Information Clinical Stage Treatment Plan
Acute Treatment‐related symptoms Surgical stage/Systemic Treatment
Follow‐up Treatment Summary
Services/ProcessesServices/Processes• Automated Risk Assessment• Quality Improvement• Registry ReportingCli i l R h
Continuous Learning System
Automated Outcomes Tracking and Feedback
• Clinical Research• Trial Matching and Registration• Internal Registries• Automated services for patient/order set
yo Genetic Counselingo Peer Supporto Smoking Cessationp
• Exchange of data for trials (eSource)• Community Networks/Services
o Social Worko Psycho-Oncologyo Life Training
Generic Patient Engagement PlatformGeneric Patient Engagement Platform
• Partnership with Salesforce– Chose leading customer relationship management (CRM) service provider
• Goal to develop patient relationship p p pmanagement (PRM) system
• Architected with patients at the center
Good quality clinical care, clinical trials, registries, quality improvement, researchers, scientists, payors, regulators and others all require the same data elements...
T i l
ClinicalTrials
Clinical
Registries
Personalized Care
WISDOM
Trial Matching
Regulators
ClinicalEfficiency
Others
Use the ‘right’ dataDecision
Care
EMA
eSourceWidget
many times Supportg
PatientEngagement
Athena
Home C
Biomedical Research
Payors
Enter the ‘right’ data onceUsing dynamic XML‐based
CareBiopharma& Device Orgs
AncillaryPatient CareSystems
checklists for data capture, rendering using IHE RFD first (and later IHE SDC) standards
WHERE ARE WE TODAY?
From the Clinician’s, Researcher’s and Patient’s Point‐of‐View
Our Journey… Project INSPIRE(INteroperability to Support Practice Improvement, Disease REgistries, and Care Coordination)(INteroperability to Support Practice Improvement, Disease REgistries, and Care Coordination)
A PCORI Funded Project
D E V E L O P E D U N D E R A T H E N A T O A D D R E S S T H E D E V E L O P E D U N D E R A T H E N A T O A D D R E S S T H E I N E F F I C I E N C I E S O F A C Q U I S I T I O N O F
C A N C E R R E G I S T R Y D A T A
Both require registrars/CRCs to find, re‐enter data
What We Found: Clinical Care (3)( )
Patient workflow processes are fairly consistent across UC Sites BUTBUT
Data elements are captured and utilized inconsistently across UCs duplication missing responsibility source/location
Screening DiagnosticsTreatment Planning Treatment Follow-up
Collaboration with FDA and ONCCollaboration with FDA and ONC
A standard clinical care checklist can inform clinical care and be aA standard clinical care checklist can inform clinical care and be a tailor‐made electronic source document for (eCRF) pre‐population
HAS TO START AT THE SOURCE: CLINIC
Change theIHE
Standards
Change the Paradigm for
Integrating Care & Research
Clinician Checklists
Program Goals and Strategies Enabled by IT
So we need:
Semantically awareImprove data sharing and
We want to:
Semantically‐awareData Integration Layer
IT GovernanceModel & Rollout
p o e da a s a g a dcollaboration capabilities
Improve data combinability to maximize the value of
i f iCommon, shared, industry‐based ontologies, data
standards, and terminologies
information
Streamline work processes associated with collection, integration,
analysis and use of information
Simplified access and integration
Structured Data Capture at Point of Care(Enter once, use many times)
Improve quality of information exchange ‐ reduced variability –
write once, read many
Simplified access and integration of data analysis and collaboration tools
…
Unify clinical research, clinical care and discovery (bench‐to‐bedside)
into a seamless continuum
…IT SolutionsGoals, Strategies
HQS
HEALTH QUESTIONNAIRE SYSTEM
Unique Features of HQSUnique Features of HQS
• Questionnaire builder with skip/branch logicQuestionnaire builder with skip/branch logic
• Versioning of questions, surveys, questionnairesquestionnaires
• Pre‐population and the ability to determine h lwhat to pre‐populate
• Customized reports generated from patient answers– sent back to patients, providers and EHR
Generic Patient Engagement PlatformAth D t tiAthena Demonstration
ID Generation
SMART Randomization
Engineg
Personalized Patient Portal
Platform slide
Patient Data CollectionPatient Data CollectionMultiple access points – web and mobile
Platform slide
Customized Patient Risk Report (Prevention)Customized Patient Risk Report (Prevention)
Platform slide
Trigger for Referrals (Breast Clinic)Trigger for Referrals (Breast Clinic)
Automatic referrals to servicesservices triggered
Platform slide
Data and Analytics – Dashboard Sample
Platform slide
TIMES ARE CHANGINGEveryone will have to play their part to drive change . . . .
TIMES ARE CHANGING
The Clinical Trials & IoT ForumThe Clinical Trials & IoT Forum
• Pharma clinical trials can take advantage ofPharma clinical trials can take advantage of new opportunities to – collect better data and– improve the patient experience; – Use devices for data collection, warehousing, analysis, utilization
• 68.1 MILLION WEARABLE DEVICES WILL BE SHIPPED THIS YEAR – 61% are for medical conditions
Concept Diagram from 2002
Center of Excellence in Breast Cancer Care
Today
Center of Excellence in Breast Cancer Care
Science Clinic
Our Plan
The advancement of science and clinical practice necessarily practice necessarily should constrain and inspire each other
Center of Excellence in Breast Cancer Care
Science Clinic
Tailor Treatment toBiology Patient PreferenceBiology, Patient Preference,and Performance
to improve outcomes
Center of Excellence in Breast Cancer Care
A Center to Accelerate Learning A Center to Accelerate Learning by Integrating Clinical Care and Research
CALM aims to transform medicine by developing and sharing tools and
An initiative of . . . Quantum Leap Healthcare Collaborative
CALM aims to transform medicine by developing and sharing tools and processes to integrating research and clinical care to enable a continuous
learning system and precision medicine for every patient
C e n t e r f o r A c c e l e r a t e d C . A . L . M .L e a r n i n g i n M e d i c i n e
Leverage Existing InfrastructureLeverage Existing Infrastructure
eSource
ATHENAATHENA I‐SPYI‐SPY BCTORG &BCTORG & CLINICALCLINICAL
eSourceChecklist
ATHENA PLATFORMATHENA
PLATFORMI‐SPY
PLATFORMI‐SPY
PLATFORMBCT.ORG & CTMATCH PLATFORMS
BCT.ORG & CTMATCH PLATFORMS
CLINICAL CHECKLISTS & eSOURCE PLATFORM
CLINICAL CHECKLISTS & eSOURCE PLATFORM
Questionnaire, Patient Driven
Metrics, Decision
Questionnaire, Patient Driven
Metrics, Decision
Clinical Trial Facilitation, Operations,
Data
Clinical Trial Facilitation, Operations,
Data
Precision Trial Matching
Precision Trial Matching
Clinician entry of the right data, at the
Clinician entry of the right data, at the
Support Support Management and
Randomization
Management and
Randomization
right time. “enter once, use many”
(v1 in )
right time. “enter once, use many”
(v1 in )development)development)
Data Gathering Data Analysis Action INTEGRATED PLATFORMS
Hypothesis‐ New Data New Analysis New Hypothesis
ACCELERATE KNOWLEDGE TURNS