Personalized Medicine: Current and Future Perspectives

Patricia Deverka, MD, MBeDuke University, Institute for Genome Sciences and

PolicyRick J. Carlson, JD

University of Washington

Background

• Pat Deverka– Fellow at Duke’s Center for Genome Ethics, Law and Policy– Member of PMC– Preventive Medicine, outcomes research, health economics

research, bioethics– Industry experience

• Rick Carlson• --Clinical Professor, Department of Health Services, Affiliate

Professor, Department of Pharmacy, School of Public Health, University of Washington

• --Advisor, Public Policy, UW Genomics Research Projects; • --Advisor on Stakeholder positions, CDC, HRSA, NHGRI• --35 years, Health Care industry experience

Personalized Medicine

• What is It: definitions

• What are some examples

• What are the key issues confronting health care system stakeholders

• What are the major policy issues

• What does it mean for you

What Is It?

• Personalized health care is a broad term for interventions that are targeted to individuals based on their risk in order to provide a more coherent and focused approach to health care. Personalized health care includes preventive, diagnostic, and therapeutic interventions, with risk defined through genetics as well as clinical and family histories.*

• More technology-focused definition relies on use of molecular testing to define risk, e.g., genetics, genomics, proteomics, metabolomics, etc.

• Goals include greater effectiveness and efficiency of health care delivery as well as improved health outcomes and quality of life

*Kathyrn Phillips, UCSF

Personalized Medicine: Vision vs. Reality

• Disruptive developments in science and technology

• Convergence of molecular biology, genetics, advanced technology, bioinformatics, broadband

• “Team science”• Transformational changes in medicine

– Molecular-based products and services– Shift towards prevention – Reclassification of disease – Integration and coordination– IT solutions; Interoperability – Consumer-centered– Premise that knowledge will change behavior

• Huge public & private investments in R&D• Health as a national asset• Ethical, legal and policy issues addressed in

parallel with the science

• Healthcare delivery focused on “sick care”– Standardization for quality improvement

• Fragmented, lack of coordination• Costs growing and unsustainable

– Pressures of expensive new technologies– Aging population in search of new services– Millions of Americans under- or uninsured

– Employer-based system tenuous– No evidence of healthier citizenry

• Inefficient use of information– Lack of IT investment, connectivity

• Evidence base for medicine inadequate– Continuing debate about role of cost-effectiveness

• Huge provider knowledge gaps re genomics• Complicated regulatory framework• Reimbursement hurdles and uncertainties• Powerful stakeholders in current system resist

change

©2005 RALPH SNYDERMAN

Tools Needed for Prediction and Personalized Care

Dis

ease

Bur

den

Time

Cos

t

1/re

vers

ibili

ty

Typical Current

Intervention

Earliest Clinical

Detection

Earliest Molecular Detection

Initiating Events

Baseline Risk

Decision Support Tools:

Baseline Risk Preclinical Progression

Disease Initiation and Progression

Assess Risk Refine Assessment Predict/Diagnose Monitor Progression

Predict Events

Inform Therapeutics

Sources of New Biomarkers:

Stable Genomics: Single Nucleotide Polymorphisms (SNPs) Haplotype Mapping Gene Sequencing

Dynamic Genomics: Gene ExpressionProteomics Metabolomics Molecular Imaging

Therapeutic Decision Support

©2005 RALPH SNYDERMAN

Prospective Health Care

Risk Assessment and Decision Support Tools

Personal Lifestyle Plan

Disease Management

Risk Modification

Dis

ease

Bur

den

Time

Low Risk High Risk

Early Chronic

Cos

t

1/re

vers

ibili

ty

Personalized Health Plan

Late Chronic

Participating Population

What are some examples?

Biomarker Application

Her-2/neu receptor Select Herceptin (trastuzumab) for breast cancer

BRCA1/2 Breast and ovarian cancer inherited risk, prophylactic tamoxifen and surgery

Transcriptional profile – 21 genes Avoid use of chemotherapy in breast CA patients with low risk of recurrence

CYP2D6/CYP2D19 Guide prescribing/ adjust dose of ~25% of commonly used drugs

VKOR/CYP2C9 Dosing of warfarin

The Leading Edge: Pharmacogenomics (PGx)

• Using an individual’s genetic profile to predict response to certain drugs

• Clinical goal is to enable better drug treatment decisions and safer medical care

• Pharmaceutical industry goal is to develop more predictable and more effective drugs

• Genetic tests already in use to predict patient response to therapy in the fields of cancer and infectious disease

• PGx has the potential to revolutionize how drugs are developed and prescribed in the future

• Faces fewest hurdles to clinical integration because does not require major healthcare delivery system redesign

Key distinctions between PGx testing and traditional genetic testing

Disease predisposition testing often does not have an obvious treatment

For PGx testing, an FDA approved drug is the treatment - goal is an adjustment in what managed care is already covering

Less likely to create new consumer demand for services

PGx more likely to be cost-effective in short-term as the treatments and alternatives are known

If PGx testing has adequate +/- predictive value, may be unethical to prescribe without testing

Key Stakeholder Positions

Private Payers

• Poor understanding of genomics;• Poor and inconsistent technology assessment• Apprehensive about specialty drug prices• Most don’t see the business case yet• Assessing proportional value for diagnostic

health information• More prepared for PGx than predictive testing

Decreased healthcare costsDecreased healthcare costsAvoid use of expensive drugs in Avoid use of expensive drugs in

non-respondersnon-respondersSave patients avoidable adverse Save patients avoidable adverse

effectseffectsImprove complianceImprove compliance

Improved health outcomesImproved health outcomesSystem cost offsetsSystem cost offsets

Decreased healthcare costsDecreased healthcare costsAvoid use of expensive drugs in Avoid use of expensive drugs in

non-respondersnon-respondersSave patients avoidable adverse Save patients avoidable adverse

effectseffectsImprove complianceImprove compliance

Improved health outcomesImproved health outcomesSystem cost offsetsSystem cost offsets

Increased healthcare costsIncreased healthcare costsHigher drug pricesHigher drug prices

Expanded patient populations for Expanded patient populations for drugsdrugs

Enforcement of privacy Enforcement of privacy safeguardssafeguards

Extended patent protectionExtended patent protectionDiagnostic tests requiredDiagnostic tests required

Increased healthcare costsIncreased healthcare costsHigher drug pricesHigher drug prices

Expanded patient populations for Expanded patient populations for drugsdrugs

Enforcement of privacy Enforcement of privacy safeguardssafeguards

Extended patent protectionExtended patent protectionDiagnostic tests requiredDiagnostic tests required

Payer perspective: what will be the impact of pharmacogenomics on total healthcare costs?

Providers, Physicians

• Lack of genetics literacy• Intensifying payer pressures for evidence-based

practice and the lag in Genomics R&D• Lack of IT designed for docs, “how to deliver”

genomics; specialization or primary care• The problematic economics of personalized

medicine; will reimbursement match the time it takes to target?

Developers of Bio-Pharmaceutical Products and Services

• Need to make the business case payers won’t make for them;

• Quantifying the value of information;

• Work out relationships between Rx and DX;

• Participate vigorously in policy for technology assessment and regulatory model development.

Government

• Need for proactive policy

• Lead IT and standardization

• CMS to jawbone; fix the FDA

• Proportionate funding for “translational” work

• Keep pushing IT and align IP with genomics agenda

• Facilitate early bioethics dialog

Consumers

• First, distinguish between those who are sick and everyone else; very differing views; both to be respected

• Beginning to “think” genetics• Need for trusted information, access and choice• Fears of exploitation, aggravation of existing

disparities, and job and health care discrimination

• Bio-engineering soon?

Emerging ethical, legal, policy ( ELP) issues

ELP concerns in clinical research

• Informed consent in the era of DNA banking• Privacy and confidentiality concerns

– Degree of anonymization is critical– Procedures to limit unauthorized disclosures– Potential for discrimination

• Harms to families or groups– Collateral information– Race-related information

• Stratification – Orphan subgroups– Genetically homogenous groups resulting in less safety data

• Incentive structure– IP issues– Focus by pharmaceutical companies on new drugs, rather than

marketed drugs (branded and generic)

PGx research requires creation of biorepositories linking genotypic and

phenotypic information– Informed consent framework adapting to unique aspects of biorepositories– Shift in emphasis from protecting subjects from physical harms to primarily

informational harms – Consent to all unspecified future research studies (blanket consent) may not be

considered sufficient to meet the standards of informed consent• Difficulties associated with reconsent procedures

– Exclusive focus on the individual research subject is arbitrary from an ethical standpoint

– Recognition of potential for group harms, even with anonymized samples– Debate over the importance of research participants having some measure of

control over the research done with their stored tissue– Narrow criteria for recontact and disclosure of results

• Do investigators have a duty to contact participants years after a study is completed?– Separation of informed consent for collection and storage of tissue samples for

PGx testing from participation in clinical trials

ELP issues in clinical practice• Marketplace introduction of PGx testing without adequate validation

– Lack appropriate regulatory framework– Failure to define a clinically and economically relevant evidence base for PGx tests and test-

drug combinations• Suboptimal access to and use of PGx testing

– Professional and payer knowledge gaps about genetics– Defining physician obligations to offer a PGx test and obligations to follow PGx test results

Liability – Physicians, pharmacists, pharmaceutical companies

• Testing without adequate consent• Inappropriate uses of PGx testing as a result of direct marketing (DTC advertising)• Secondary information conveyed by PGx results that may produce psychosocial

harms– Likelihood of other diseases; Progression of current disease– Unsolicited information about family members

• Discriminatory uses of PGx information by third parties– Insurers/Employers - based on belief that disease cannot be adequately treated given

currently available therapies or based on knowledge of disease predisposition• Higher drug costs leading to barriers to access

Rapid and unmanaged introduction of genetic tests into marketplace

• Inappropriately induces demand for services• Hype

– Reinforces notion of genetic determinism and essentialism

• Predictive values of PGx tests may be too low to be clinically useful– Shift public and private resources away from more effective

ways of improving public health

• Lack of information about PGx tests may lead to real harms to patients by physicians and payers– Inaccurate test results– Poor counseling from physicians (unable to accurately interpret

test results)– Coverage policies that are not justified by the science

When might direct consumer access to PGx testing be permissible?

• When tests meet appropriate standards of analytic and clinical validity and results are conveyed in an accurate and understandable manner

• When test contains information about response to over-the-counter drugs, dietary regimens, etc

• When individual has insurance coverage for the drug, but not the corresponding PGx test

• When individuals are concerned about stigmatization or discrimination

• DISSENTING OPINION: None of the above.

What Are the Major Policy Issues?

• Costs, overall, and specialty drugs---constraints on research

• Regulatory reform• Access and equity concerns• The uses of genetic information• Setting levels for regulation and evidence for

public payment• Provider and consumer literacy• Significant bioethical issues.

What Does it Mean for You?

• Your experience, however painful, becomes the experience of everybody

• The economics of health care services suppress basic public research $$$’s

• An orphan disease for everyone; managed care must solve the coverage challenge of allocating resources in an era of specialty drugs

PM requires coordination across multiple stakeholders

Producers

ConsumersPGX

Diagnostic Companies

Government & Universities Biopharmaceutical Co’s

Genetics Companies

(data miners, technology co’s, etc.

Patients and HC

consumers

Healthcare Professionals Managed

Care

Payers

Ethicists, Legislators