Individualizing Patient Care through Precision Medicine: Shaping the Industry’s Future - Laura Esserman, UCSF

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


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


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


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


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


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


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


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


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


Science Clinic

Our Plan

The advancement of science and clinical practice necessarily practice necessarily should constrain and inspire each other


Science Clinic

Tailor Treatment toBiology Patient PreferenceBiology, Patient Preference,and Performance

to improve outcomes


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

Business

Individualizing Patient Care through Precision Medicine: Shaping the Industry’s Future - Laura Esserman, UCSF