Annual Meeting & ExpositionSeattle, Washington | March 22-25

Pharmacogenomic Testing: The Economics of Individualized MedicineKristin(Weitzel) Wiisanen, PharmD, FAPhABeth Devine, PhD, PharmD, MBA, FASHP

March 22, 2019

• Beth Devine – I have nothing to disclose• Kristin (Weitzel) Wiisanen – I have nothing to disclose

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Disclosures

• Target Audience: Pharmacists• ACPE#: 0202-0000-19-012-L04-P• Activity Type: Knowledge-based

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CPE Information

At the completion of this knowledge-based activity, participants will be able to:• Describe the basics of pharmacogenomics and pharmacogenomic testing

• Recognize the impact of genetic testing on therapy plan development

• Discuss the economic impact of genetic testing and future trends for drug development

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Learning Objectives

1. In the future, it is likely that genetic information will be:

A. Decreasingly available to individual patients

B. Increasingly used to guide population health decisions

C. Increasingly restricted by patients’ primary care providers

D. Decreasingly used to guide a patient’s individual medical care

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Assessment Questions

2. The Clinical Pharmacogenetics Consortium (CPIC) guidelines:

A. Provide guidance on using pharmacogenetic test results in practice

B. Recommend whether a test should be ordered

C. Recommend when to order a test

D. Are available for the majority of medications

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Assessment Questions

3. The cost of testing, value of a pharmacogenomics test, and insurance reimbursement for testing have implications for:

A. Which drugs have pharmacogenomic information in the Food and Drug Administration (FDA) labeling

B. Which drugs are regulated by the European Medicines Agency

C. Public policy regarding pharmacogenomic testing

D. Whether a drug is approved by FDA7

Assessment Questions

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Part 1:

Genomics/Pharmacogenomics and Public Health:

Does This Even Make Sense?

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2015 State of the Union: Precision Medicine Initiative

• Human genome is the approximately 3 billion nucleotides (comprised of 4 letters) that make up our genetic code

• Humans are about 99.8-99.9% identical

• The 0.1-0.2% is what makes us unique

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What is the human genome?

National Human Genome Research Institute (www.genome.gov)

• Human Genome Project was a large international effort to define the human genetic code• Completed in 2001; after 13 years and $2.7 Billion• Delivered one “complete” human genome

• Human genome sequencing – 2011• Costs $5000 to $20,000; and takes a couple weeks

• Human genome sequencing – 2013• Costs < $1000 and can be completed in < 1 day

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Human Genome Project

National Human Genome Research Institute (www.genome.gov)

• Expected that genetic data will increasingly be available on patients• 10 million have done direct to consumer (DTC) genotyping• Expected to be 100 million by 2021

• In the future, a person’s genome sequence will likely be part of their medical record• By 2025 whole genome sequencing expected in 60 million

• At core of concept is one-time nature of genotyping and as needed availability of genetic information

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Human Genome Sequencing and Precision Medicine

National Human Genome Research Institute (www.genome.gov)

• Use of information about an individual, including their family history, diseases, environmental factors, genetic and other unique information to personalize or individualize care

• Disease risk prediction and diagnosis

• Cancer (tumor) genetics

• Drug therapy (pharmacogenetics)

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Precision Medicine

National Human Genome Research Institute (www.genome.gov)

• What about, “the right treatments at the right time, every time to the right person?”• Pharmacogenomics and the individual

• Increasing adoption of “Precision” public health• “Populations” are the units of intervention that use innovative technology and

scientific discovery to improve outcomes

• The “next generation” of public health• Using pharmacogenomics and precision medicine to improve public health policy

and practice14

Pharmacogenomics and Public Health

Khoury MJ, et al. Precision public health for the era of precision medicine. Am J Prev Med. 2016;50:398-401

“… if precision medicine is about the individual, precision public health is about populations. It is

essentially about delivering ‘the right intervention at the right time, every time to the right

population.’”Muin J. Khoury,

Director Office of Public Health Genomics, CDChttps://blogs.cdc.gov/genomics/2018/05/15/precision-public-health-2/

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What is precision public health?

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Impact of Pharmacogenomic Testing on Populations

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Impact of Pharmacogenomic Testing on Populations

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Part 2

Assessing the Evidence and the Current Landscape

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Progress of Genetic/Genomic Testing

Single Nucleotide

Polymorphism (SNP) = Single

Gene Test

Multi-Gene Panel =

Tests multiple genes for a

single indication

Next Generation Sequencing

(NGS) = Measures

multiple genes using high speed DNA sequencing technology

Whole Exome Sequencing =

Evaluates entire exome

(coding regions of the

genome)

Whole Genome

Sequencing = Evaluates

entire genome

Time

Must be supported by evidence of:

1) Analytic validity2) Clinical validity

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Progress and Types of Genetic/Genomic Testing

Risk assessment, screening, diagnosis, monitoring of progression

Target or manage medication therapy = pharmacogenomics

Germline biomarkers

Somatic biomarkers (derived from tumor tissue)

Preemptive Reactive

Must be supported by evidence of

clinical utility

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Genetic Variation: Drug metabolizing enzymes

• Evaluation of Genomic Applications in Practice and Prevention (EGAPP)• Established by Centers for Disease Control (CDC) Office of Public Health

Genomics• Develop systematic processes for evidence-based assessment of genetic tests

and genomic technology• Clinical Pharmacogenetics Implementation Consortium (CPIC)

• Provide guidance on using pharmacogenetic test results in practice instead of advising whether or not a test should be ordered

• Dutch Pharmacogenetics Working Group• Food and Drug Administration drug product labeling

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An Evidence-Based Approach to Pharmacogenomics

Teutsch SM, et al. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet Med.2009;11:3-14.Caudle KE, et al. Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process. Curr Drug Metab. 2014 Feb;15:209-17.

• Analytic validity

• Clinical validity

• Clinical utility

• Ethical, legal, and social implications

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Evidence-based criteria for evaluating tests

Scott SA. Personalizing medicine with clinical pharmacogenetics. Genet Med. 2011;13:987-95.

• Likelihood that a test result will alter clinical outcomes or treatment strategies• Usefulness, changes in health outcomes

• Third-party payers increasingly rely on evidence of clinical utility for reimbursement for pharmacogenomic tests

• Utility of test varies based on associated drug therapy and indications (e.g., CYP2C19 testing for clopidogrel)

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Clinical Utility

• Level of evidence required for a test to achieve clinical utility• Gold standard = randomized, controlled trial• Limitations in conducting randomized controlled trials in pharmacogenomics

• Sampling issues• Technology limitations (e.g., different testing platforms)• Low prevalence of targeted clinical outcome or variant allele

• Pharmacogenomics studies• Focus on incremental advantages in safety and efficacy in targeted patients• “Identifying the outliers”

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Clinical Utility

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Evidence of Clinical Validity for PGx Biomarkers in FDA Labels

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Evidence of Clinical Utility for PGx Biomarkers in FDA Labels

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Treatment Recommendations in FDA Drug Labels

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Trends in Strength of Evidence in 137 FDA Labels (Germline Biomarkers)

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Major European Initiative: Ubiquitous PGx (U-PGx) Consortium

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Translating Evidence Into Practice: IGNITE Network Example

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention (PCI)

Kaplan-Meier Survival Estimates of MACE in Relation to CYP2C19 Genotype and Antiplatelet Therapy

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A Case for Preemptive Genotyping:The Vanderbilt PREDICT Project

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A Case for Preemptive Genotyping:Claims Database

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Trends in Proportion of Index Medication Orders for which PGx Test Drawn

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Part 3:

Estimating the Value of PGx Tests

• Cost effectiveness analysis (CEA) • Outcome expressed in natural units

• Cost utility analysis (CUA) – type of CEA• Outcome expressed in quality adjusted life years (QALYs)

• Model inputs• Costs• Outcomes (clinical utility of PGx)

• Efficacy, safety, health-related quality of life• Benefit/risk trade off

• Probabilities• Calculate incremental cost-effectiveness ratio (ICER)

• ICER = ) 38

Brief Primer on Value Assessment in Health Economics

• Costs (Cpgx) – sample collection, analysis; patient/provider education• Probability (Pvar) – patient will have clinically relevant variant• Probability (Pdrug) – patient will be exposed to drug affected by variant• *Incremental clinical benefit (Bpgx)– improving effectiveness, avoiding harm,

per patient tested and receiving drug• Probability (PO) patient experiences the outcome• Measured in quality-adjusted life years (QALYs)

• *Incremental healthcare costs (Csav) – saved or spent by improving effectiveness or avoiding harm, per patient tested and receiving drug

*Complex to estimate

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Estimating Value for PGx using CEA

Veenstra DL. The value of routine pharmacogenomic screening-Are we there yet? A perspective on the costs and benefits of routine screening-shouldn't everyone have this done? Clin Pharmacol Ther. 2016;99:164-6.

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Value Landscape of PGx Screening

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Cost-effectiveness of Guideline-dosed warfarin, PGx-Warfarin and Direct Oral Anticoagulants (DOACs)

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Risk-Benefit Analysis of Clopidogrel, Prasugrel (PGx) in Acute Coronary Syndrome (ACS)/PCI

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Risk-Benefit Analysis of Clopidogrel Prasugrel (PGx) in ACS/PCI

Reference Average clinical benefit per patient tested and receiving drug (QALYs)

Pink J, et al. Cost-effectiveness of pharmacogenetics-guided warfarin therapy vs. alternative anticoagulation in atrial fibrillation. Clin Pharmacol Ther. 2014;95;:199-207 (PMID: 24067746)

0.003

Guzauskas GF, et al. A risk-benefit assessment of prasugrel, clopidogrel, and genotype-guided therapy in patients undergoing percutaneous coronary intervention. n Pharmacol Ther. 2012;91:829-837 (PMID: 22453194)

0.05

Rattanavipapong W, et al. Economic evaluation of HLA-B*15:02 screening for carbamazepine-induced severe adverse drug reactions in Thailand. Epilepsia2013;54:1628-1638 (PMID 23895569);Dong D, et al. Cost-effectiveness of HLA-B*1502 genotyping in adult patients with newly diagnosed epilepsy in Singapore. Neurology 2012;79:1259-1267 (PMID 22955130)

0.02 to 0.03

Schackman BR, et al. The cost-effectiveness of HLA-B*5701 genetic screening to guide initial antiretroviral therapy for HIV. AIDS 2008;22:2025-2033 (PMID 18784465)

0.003

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Quality Adjusted Life Year (QALY) Gains

Veenstra DL. The value of routine pharmacogenomic screening-Are we there yet? A perspective on the costs and benefits of routine screening-shouldn't everyone have this done? Clin Pharmacol Ther. 2016;99:164-6.

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Value: Cost-Utility Analysis of Multi-, Single, No PGx Testing for ACS/PCI Patient

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Cost-Utility Analysis of Multi-, Single, No PGx Testing for ACS/PCI Patient

Hart MR. Exploring Strategies to Optimize the Value of PGx Testing. University of Washington. ProQuest Dissertations Publishing, 2018. 10828141.

MPGx = Multigene panelSPGx = Single gene panelQALY = quality-adjusted life yearICER = incremental cost-effectiveness ratioNet monetary benefit (NMB) based on $100,000 willingness-to-pay (WTP) per QALY

Mean Cost Incremental Cost

QALY Incremental QALY

ICER (cost/QALY)

Net Monetary Benefit*

Multi PGx Test

$13,275 0.97 $5,656 (SPGx);

$28,391(No PGx)

Single PGx Test

$14,921 -$1,646 0.93 0.04 Dominated by MPGx

No PGx Test

$24,643 -$11,368 0.80 0.17 Dominated by MPGx

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Cost-Utility Analysis of Multi-, Single, No PGx Testing for ACS/PCI Patient

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Cost-Utility Analysis of Multi-, Single, No PGx Testing for ACS/PCI Patient

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Value: Modeling Costs of Clinical Decision Support (CDS) for PGx

Variable Low Current HighInitial cost for single rule $4000 $6600 $7500Maintenance rate (proportion of initial cost)

10% 20% 25%

Patients with testing per institution 200 500 41250Number of rules 3 9 300Probability rule fires for patient 0.25% 1% 2%Efficiency for additional rules 70% 80% 85%Number of institutions 2 10 500Efficiency for additional institutions 70% 99% 100%

Mathias PC, et al. Modeling the costs of clinical decision support for genomic precision medicine. AMIA Jt Summits Transl Sci Proc. 2016;:2016:60-4.

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Modeling Costs of Clinical Decision Support (CDS) for PGx

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Part 4:

Policy Implications of Pharmacogenomics

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Next Generation Sequencing (NGS)

Single Nucleotide

Polymorphism (SNP) = Single

Gene Test

Multi-Gene Panel =

Tests multiple genes for a

single indication

Next Generation Sequencing

(NGS) = Measures

multiple genes using high speed DNA sequencing technology

Whole Exome Sequencing =

Evaluates entire exome

(coding regions of the

genome)

Whole Genome

Sequencing = Evaluates

entire genome

Time

Must be supported by evidence of:

1) Analytic validity2) Clinical validity

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CMS Covering Next Generation Tumor Sequencing (NGTS)

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Practical Resources for Reimbursement

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Horizon Scan of Clinical Laboratories offering PGx Testing

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RCT of PGx-CDS in Home Health Patients

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Steps to Implement Preemptive PGx

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Steps to Translate PGx Result into Clinically Useful Action

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The Genomics Enabled Learning Healthcare System

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Part 5:

Pharmacist Reimbursement – Emerging Practice Models and Trend

• Non-academic, community based health systems

• Physician- or pharmacist-led outpatient clinics

• Community pharmacies

• As a component of Medication Therapy Management or other established pharmacy services

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Building Momentum for Emerging Practice Models

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Northshore University Health System: Multidisciplinary Pharmacogenomics Clinic

Dunnenberger HM, et al. Implementation of a multidisciplinary pharmacogenomics clinic in a community health system. Am J Health Syst Pharm. 2016;73:1956-1966.

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Northshore University Health System: Multidisciplinary Pharmacogenomics Clinic

Dunnenberger HM, et al. Implementation of a multidisciplinary pharmacogenomics clinic in a community health system. Am J Health Syst Pharm. 2016;73:1956-1966.

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Duke University: Pharmacist-Led Medication Therapy Management (MTM) Services in Outpatient Cardiology Clinic

MTM Visit 1

• Complete medication history• Review of pharmacogenetic testing with patient• Collect blood sample

Between Visits

• Pharmacist reviews results• Discuss recommendations with cardiologist

MTM Visit 2

• Review pharmacogenetic test results with patient• Discuss recommended treatment changes based on results

Haga SB, et al. Incorporation of pharmacogenetic testing into medication therapy management. Pharmacogenomics. 2015;16:1931-1941.Haga SB, et al. Pilot study: incorporation of pharmacogenetic testing in medication therapy management services. Pharmacogenomics. 2014;15:1927-1737.

• Electronic Health Record (EHR)-driven Pharmacogenomics Consult Service• Ambulatory Pharmacogenomics Clinic

• Provider referral to clinic• Patient has 1-hour visit with pharmacist/physician-geneticist• Consult note/recommendation into EHR• Physician-geneticist bills for visit according to appropriate CPT/billing code

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Cleveland Clinic: Provider-Requested Pharmacogenomics Consultation Service

Hicks JK, et al. Implementation of clinical pharmacogenomics within a large health system: From electronic health record decision support to consultation services. Pharmacotherapy. 2016;36:940-948.

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University of Florida (UF) Health Pharmacogenetics Consult Clinic

Clinic Visit 1

• Patient education

• Medication history

• Sample collection

UF Pathology

• Analyzes sample

• Uploads results to EHR

Interpretation

• Interpretation note written by PGx pharmacist placed in patient chart

• Discussion with physician

Clinic Visit 2

• Patient report handout

• Patient education

• Medication changes

Arwood M et al. In press.

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Community-Pharmacy Based Models

Pre-Implementation: Collaborative Practice Agreement established with community physician to authorize PGx test order from pharmacy

Patient Identification: At point of dispensing history

Pharmacist Visit 1: Medication history and buccal swab for commercial lab PGx testing

Between Visits: Pharmacist receives result; recommendations communicated to physician by fax or telephone; response communicated to pharmacist

Pharmacist Visit 2: Pharmacist reviews recommendations and drug therapy changes; Visits billed using pharmacy-specific MTM codes

Ferreri SP, et al. Implementation of a pharmacogenomics service in a community pharmacy. J Am Pharm Assoc (2003). 2014;54:172-180. Kisor DF, et al. Pharmacogenetics in the community pharmacy: thienopyridine selectin post-coronary artery stent placement. J Pharm Pract 2014;27:416-419.Gibson ML, et al. Pharmacogenomics testing in a community pharmacy: patient perceptions and willingness-to-pay. Pharmagenomics. 2017;18:227-233.

• May be driven by single pharmacist or group• Partner with commercial laboratories

• Perform pharmacogenetic testing• Coordinate prior authorization for testing• Provide upfront, out-of-pocket price to patient based on sliding scale

• Focused on outpatient, clinic-based setting• Incorporate reimbursement for pharmacist time/service• May not focus on single gene-drug pairs • May expand recommendations beyond CPIC guidelines • May utilize external software/services for interpreting and applying test results to

patient care68

Trends/Characteristics of Emerging Practice Models

• Potential Practice Models• Collaborative practice agreements

• Standing order or protocol-based

• Medication Therapy Management

• Value-Based Care (e.g., pharmacist supports practice’s ability to meet quality or other measures that affect provider reimbursement)

• Self-funded mechanisms (e.g., executive health or self-insured programs)

• Fee-for-service 69

Explore Ways to Incorporate PGx into Established Models of Pharmacist Care

• Potential Factors Influencing Pharmacist Compensation• Individual State Rules or Regulations

• Pharmacist scope of practice• Collaborative drug therapy agreements• Pharmacist provider status

• Individual Practice Setting• Physician office• Clinical service integrated into health system infrastructure• Community pharmacy

• Patient population• Outpatient vs. inpatient• Medicare vs. other payers• Disease states and medication use

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Explore Ways to Incorporate PGx into Established Models of Pharmacist Care

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Opportunities for Pharmacists: Provider Status

• Mountain Area Health Education Center/University of North Carolina at Chapel Hill• Pharmacist-provided AWV (including all Medicare-required components) and CMM

with additional CMM visits at 3 and 6 months• Return on Investment (ROI) analysis demonstrated positive net gain of $2,644 and an

ROI of 38.1%

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Example: Annual Wellness Visit (AWV) and Comprehensive Medication Management (CMM)

Woodall T, et al. Provision of annual wellness visits with comprehensive medication management by a clinical pharmacist practitioner. Am J Health Syst Pharm. 2017;15:218-223.

• Major initiatives are underway• Although uptake of PGx into clinical practice has been slow, momentum

is building for newer practice models• We are making progress - multigene panels, NGS are here to stay

• Policy Initiatives to facilitate adoption:• Improve the evidence base• Address uncertainty• Facilitate implementation• Continue to estimate value

73

Conclusions

Veenstra DL. The value of routine pharmacogenomic screening-Are we there yet? A perspective on the costs and benefits of routine screening-shouldn't everyone have this done? Clin Pharmacol Ther. 2016;99:164-6. Ginsburg GS, et al. Precision medicine: From science to value. Health Aff (Millwood). 2018;37:694-701.

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Assessment Questions

1. In the future, it is likely that genetic information will be:

A. Decreasingly available to individual patients

B. Increasingly used to guide population health decisions

C. Increasingly restricted by patients’ primary care providers

D. Decreasingly used to guide a patient’s individual medical care

Objective 1: Describe the basics of pharmacogenomics and pharmacogenomic testing

75

Assessment Questions

2. The Clinical Pharmacogenetics Consortium (CPIC) guidelines:

A. Provide guidance on using pharmacogenetic test results in practice

B. Recommend whether a test should be ordered

C. Recommend when to order a test

D. Are available for the majority of medications

Objective 2: Recognize the impact of genetic testing on therapy plan development

76

Assessment Questions

3. The cost of testing, value of a pharmacogenomics test, and insurance reimbursement for testing have implications for:

A. Which drugs have pharmacogenomic information in the FDA labeling

B. Which drugs are regulated by the European Medicines Agency

C. Public policy regarding pharmacogenomic testing

D. Whether a drug is approved by FDA

Objective 3: Discuss the economic impact of pharmacogenomic testing and future implications for policy development.

77

Thank You!

Questions?