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Getting Pharmacists Into Pharmacogenomics:
What’s Been Going on and What to Expect
James Lee, PharmD, BCACPClinical Assistant Professor
Co-Director, UI Health Personalized Medicine ProgramUniversity of Illinois at Chicago College of Pharmacy
University of Illinois Hospital & Clinics
Objectives
1. Describe the background and rationale for precision medicine.2. Identify opportunities and challenges to pharmacogenetic (PGx)
testing expansion and the clinical resources available to pharmacists.
3. Describe implications and issues surrounding direct-to-consumer (DTC) genetic testing.
4. Describe the pharmacist’s role in pharmacogenetic testing and patient education.
Disclosures
I have nothing relevant to disclose.
Any branded products, services, and images shown in this presentation are for illustrative and demonstrative purposes only. I do not endorse and am not promoting any of these entities, products, or services.
Today’s Standard Approach
One Drug/Dose Fits All
Good Effect No Effect Adverse Outcome
XX
A Tailored Approach
Dose A
Good Effect Good Effect Good Effect
Dose B Dose C orAlternate
Agent
POORmetabolizers
INTERMEDIATEmetabolizers
NORMALmetabolizers
Personalized Medicine
Precision Medicine
Precision Health
What’s in a Name?
An Approach to Treating, Managing & Preventing Disease
PRECISION HEALTH
🏃🏃Lifestyle
💊💊Genome
Pharmacogenomics
🌴🌴Environment
Pharmacogenomics: Why It’s Important
Reality of medications• Drugs can be dangerous• Drugs cost money and are expensive (non-adherence, wastage, new therapies)
Established scientific basis of PGx• Known impact of genetic influence on drug pharmacokinetics, pharmacodynamics
New and quality real-world evidence show clinical utility with commonly used medications
Many resources available to help clinicians apply PGx in clinical practice
8
PGx Testing Trends
Next generation sequencing • Whole exome sequencing• Whole genome sequencing
Variant-specific testing• Testing specific SNP(s) of interest• Currently more common than NGS
9
Single Nucleotide Polymorphisms (SNPs)
• Most common type of genetic variation• >1% frequency in the population• Single nucleotide substitution
• May impact pharmacokinetic and pharmacodynamic response
Timing of Testing
Preemptive Reactive
Healthy patient on no medications
Patient starting antidepressant therapy & multigene PGx panel is available
Patient undergoing PCI started on clodidogrel and tested for CYP2C19
Patient failed all therapies and PGx testing performed to identify cause
How Should We Use PGx?
An additional tool to help solve medication challenges
IMPROVEmedication selection/
dosing
Achieve treatment outcomes
FASTER
REDUCE• Medicine waste• Medicine cost• ADR exposure• Readmissions• Etc
12
What is PGx Not?
13
Opportunities & Challenges to expanding PGx testing
Promoting patient safety as a strategy
• Focus on preventing patient harm• Inject up-to-date clinical evidence into the conversation• Build allies and get different groups of people involved
15
Challenges
An “emerging” science• Low quality and limited literature in narrow populations (European, Asian)• Impact on clinical outcomes are still emerging, some mixed.
Inconsistent, unclear, and patchwork regulation• Evolving regulatory changes, pressure, reach • Questions re: test development, regulation• Multiple agencies involved w/ contradictory stances
ChallengesWHEN is it appropriate to test
• Conservative nature of clinical practice guidelines lack of PGxrecommendations
HOW to test• Appropriate test for a specific patient vs. a population• Single vs. multi-gene testing• Pre-emptive vs reactive• Result turnaround time• Getting interpretable results and recommendations to providers (and patients?)
Testing cost• Viewpoint: Short-term cost vs long-term investment• Evolving reimbursement
Ethical & Legal Concerns
Information access, discrimination, patients’ use of own genetic info• Disease predisposition• Philosophical issues: origins, meaning, and behaviors in life• Reproductive rights• Gene therapy and germline engineering• Patenting: genetic sequences and human-made organisms
Patient privacy, autonomy, confidentiality
18
GINA 2008: Genetic Information Nondiscrimination ActProhibits requiring genetic information to determine:
• Employment decisions• Health insurance coverage, rates or pre-existing conditions
“Genetic information”:• Individual genetic test results• Family member’s genetic test results up to 4th degree relatives• Fetus, embryo, or pregnant family member’s genetic test results• Family history of disease/disorder• Requests for genetic testing services
19Government Publishing Office. https://www.govinfo.gov/content/pkg/PLAW-110publ233/pdf/PLAW-110publ233.pdf. Accessed 7/31/19.
GINA 2008: Genetic Information Nondiscrimination ActWhat GINA does NOT do:
• Extend to other types of insurance• Life insurance• Disability insurance• Long-term care insurance
• Mandate genetic testing• Apply to employers with < 15 employees• Prevent use of disease manifestation of disease/disorder to determine
premium rates or eligibility• Prohibit health insurance from using test results for payment determination
20Government Publishing Office. https://www.govinfo.gov/content/pkg/PLAW-110publ233/pdf/PLAW-110publ233.pdf. Accessed 7/31/19.
Human Concerns
Patients
• Health literacy and assumptions• Influence of misleading, deceptive marketing• Privacy and future use of genetic data• Genetic discrimination• Impact on family
Providers
• Attitudes: “Should we test” vs “Standard of Care”• Limited knowledge, training, experience• Guiding patient expectations and messaging• Managing patient anxiety unnecessary follow-up and costs • (?) Research ethics
21
Opportunities
Patients are interested & generally positive towards genetic testing• Minimize trial/error
• Selecting medications• Guiding dosing• Avoiding ADRs
• Predict side effects, explain past reactions• Curiosity / novelty
22Haga et al. Pharmacogenomics J. 2012;12(3):197-204.Lemke et al. Pharmacogenomics. 2018;19(4):321-331.
Opportunities
Ever expanding # medications where PGx is thought to matter • >300 gene-drug pairs identified• ~200 drugs with FDA labeling• ~130 “recommended” or “actionable” PGx variants
Higher quality evidence rapidly emerging • Multi-site, prospective, randomized, or pragmatic trials• Larger sample size• More diverse range of ancestries
Improving reimbursement landscape• Ex: CYP2C19, DPYD, TPMT, HLA-B, CYP2D6, VKORC1
NHGRI. The Cost of Sequencing a Human Genome. Available at www.genome.gov/sequencingcosts
Opportunities
Improved ease of specimen collection (e.g. buccal swabs)
Improve drug selection, management, outcomes• Ex: clopidogrel, warfarin, antineoplastic agents
Focus on cost containment• Drug waste• Preventable admissions and readmissions• Mortality
OpportunitiesManaging Gene-Herbal-Drug Interactions?
Metabolized by CYP450? 1A 2B6 2C19 2C9 2D6 3A4 3A5
Black Cohosh INH INHGarlic 2E1 IND INDGinger Yes, unspecified INH INH INHGingko 2D6 INH INH INH INDGinseng 3A4 INH INH INH INHGoldenseal INH INH INHGreen Tea IND INH INH INHLicorice IND INH INDMilk Thistle INH INH INHSt John’s Wort Yes, unspecified IND IND IND
Wieruszewk et al. Consult Pharm 2017;32(2):99-104. PMID 28569661
Predicted Phenotypes
Drug Metabolism• Poor – Intermediate – Normal – Rapid – Ultra-Rapid… METABOLIZER
Drug Transporter Function• Poor – Decreased – Normal – Increased… FUNCTION
Human Leukocyte Antigen Carrier Status• Carrier or Positive• Non-carrier or Negative
Common PGx TestsDrug Metabolism & Transporter Function
• CYP2D6: TCA/SSRI (dosing/selection), codeine (toxicity: conversion to morphine)• CYP2C9: warfarin (w/ VKORC1: dosing), phenytoin (w/ HLA-B*15-02)• CYP2C19: TCA/SSRI (dosing/selection), clopidogrel (bioactivation), voriconazole
(dosing)• DPYD: fluoropyrimidines (toxicity)• TPMT: thiopurines (toxicity)• SLCO1B1: simvastatin (myopathy)
Human Leukocyte Antigen Carrier Status hypersensitivity• HLA-B*57:01: abacavir• HLA-B*58:01: allopurinol • HLA-B*15:02 / HLA-A*31:01: carbamazepine, oxcarbazepine • HLA-B*15:02: phenytoin
Genotype Nomenclature
Star-Allele Nomenclature• First system developed• *1 = reference/“normal”
function/wildtype;• Not necessarily the most common
in an ancestral group
• (Ex: Gene *Number/*Number)• CYP2C9 *1/*1 normal activity• CYP2C9 *1/*2 intermediate
activity• CYP2C9 *2/*2 low activity
HGVS/IUPAC Nomenclature • (ex: 1075A>C)• A, G, C, T nucleotides
Reference SNP Cluster ID (rs#) • (ex: rs1057910)• Accession number to refer to a
specific SNP• National Center for Biotechnology
dbSNP database
Sample Test Result
Gene Genotype Predicted PhenotypeCYP2C19 *2/*2 Poor metabolizerCYP2C9 *1/*1 Normal metabolizerCYP2D6 *1/*3 Intermediate metabolizerHLA-B*57:01 Positive High risk of hypersensitivityVKORC1 G/A Intermediate warfarin sensitivitySLCO1B1 T/T Normal function
Interpreting a Genotype
Be careful!
The allele number is specific to the functional effect of a protein a specific gene encodes
CYP2D6 *1/*2 Extensive MetabolizerCYP2C19 *1/*2 Intermediate Metabolizer
PGx Clinical Resources
PharmGKB• Annotates genetic variants, gene-drug-disease relationships, drug
pathways• Searchable by: drug, gene, variant• Very Important Pharmacogene (VIP) Summaries
• References drug labels containing PGx information• Sources: US FDA, Health Canada, EU European Medicines Agency, Japan
• PGx clinical guidelines• https://www.pharmgkb.org/guidelines• Multiple organizations: CPIC, DPWG, CPNDS
33
www.pharmgkb.org
PharmGKB PGx LevelPGx Level Definition/Drug Label Content
Testing required • States or implies some type of testing should be conducted before using the drug• Indicates a variant is an indication for the drug• Includes the wording “should be performed”
Testing recommended • States or implies some type of testing is recommended before using the drug• Includes the wording "should be considered"
Actionable PGx • Does not discuss testing but contains information about changes in efficacy, dosage, or toxicity as a result of variants
• May mention contraindication of the drug in a subset of patients but does not require or recommend gene, protein, or chromosomal testing
Informative PGx • Mentions a gene or protein involved in drug metabolism or PD, but no information to suggest that variation in the gene/protein leads to different response
PharmGKB (drug label) 2018. 34
CPIC
• Develops peer-reviewed, expert consensus guidelines• Evidence sources: preclinical functional and clinical data; disease-specific
consensus guidelines
• Accelerate PGx implementation• Assist clinicians with HOW to translate and apply PGx test results• Address implementation process and barriers
• 35 guidelines available• Continuously updated and expanded
35
www.cpicpgx.org
CPIC Guidelines: Standardized Formats
In the guideline manuscript• Table 1: Genotype to phenotype translation• Table 2: Prescribing recommendations & recommendation strength
Supplemental materials (for each guideline)• Allele definition table• Allele functionality table• Gene frequency table• Diplotype-phenotype assignment table• Informatics tables
36
37
Table 1: Genotype to Phenotype Assignment
Note: Old nomenclature New nomenclatureEXTENSIVE Metabolizer NORMAL metabolizer
38
Table 2: Prescribing Recommendations
39
CPIC GuidelinesIncludes many commonly used drugs!
• Carbamazepine (HLA-B*15:02)• Phenytoin (CYP2C9, HLA-B*1502)• Allopurinol (HLA-B*58:01)• Abacavir (HLA-B*57:01)• Warfarin (CYP2C9, VKORC1)• TCAs (CYP2D6, 2C19)• SSRIs (CYP2D6, 2C19)• Clopidogrel (CYP2C19)
• Codeine (CYP2D6)• Simvastatin (SLCO1B1)• Ondansetron (CYP2D6)• Atazanavir (UGT1A1)• Thiopurines (TPMT)• Fluoropyramidines (DPYD)• Tacrolimus (CYP3A5)• Voriconazole (CYP2C19)
40
Direct-to-Consumer Genetic Testing
Direct-to-Consumer Genetic Testing• $100-200• Advertised on TV, internet, etc.• Panel test
• Ancestry• Traits• Carrier status• Drug metabolism• Metabolic assessments
A simple process1. Order kit online2. Collect specimen(buccal swab or
spit)3. Mail kit back to testing company4. Results available in 6-8 weeks
• Online portal• Mail• Phone
What can you get tested?
Ancestry/admixture• Ancestry composition• Maternal and paternal haplogroups• DNA family/ancestry inherited from parents• Neanderthal ancestry
What can you get tested?
Traits / Likelihood• Back hair• Balding• Bitter taste reception• Cheek dimples• Freckles• Hair curliness
• Skin pigmentation• Widow’s peak• Asparagus odor detection• Toe length ratio• Earwax type• Many more…
What can you get tested?
Nutritional (nutrigenetic) & metabolic assessment (wellness)• Genetic weight• Deep sleep• Lactose intolerance• Muscle composition• Saturated fat and weight• Sleep movement• Caffeine consumption• Many more…
What can you get tested?
Carrier Status / Disease Susceptibility • Age-related macular generation, Alpha-1 antitrypsin deficiency, hereditary
thrombophilia, late-onset Alzheimer’s Disease, Parkinson’s Disease• Cystic Fibrosis, Bloom Syndrome, Beta Thalassemia, Autosomal Recessive
Polycystic Kidney Disease, Congenital Disorder of Glycosylation Type 1a, Neuronal Ceroid Lipofuscinosis, Sickle Cell Anemia, Tay-Sachs Disease, Gaucher Disease, Herlitz Junctional Epidermolysis Bullosa
• Many more…
Pharmacogenomics• Drug metabolism
What can you get tested?
The more dubious stuff…• Matchmaking / Personality Compatibility
• Biocompatibility• Neurocompatibility• Psychological compatibility• Relationship compatibility• Physical chemistry• Social alignment
• Dating apps• Book sets
Instant Chemistry: Available at: https://instantchemistry.com/. Accessed 1/1/18Pheramor: Available at: https://www.pheramor.com/science. Accessed 7/29/19
What can you get tested?
The more dubious stuff…• Inborn/Child Talent
• Optimism, risk-taking, shyness, literature, reading ability, alcoholism, sentimentality, height, sensitivity to second-hand smoke, IQ, EQ, split personality, self control, moldability, drawing, dancing, propensity for teenage romance, etc.
• Paternity / Infidelity testing• “Discreet” testing
Map My Gene: Available at: http://www.mapmygene.com/services/talent-gene-test/. Map MY Gene: Available at: http://www.mapmygene.com/wp-content/uploads/2017/05/MAP-MY-GENE-Brochure_Inggris_Singapore_FA-1.pdfAll About Truth DNA Services: Available at: http://allabouttruthdna.com/other-testing-services/infidelity-dna-testing. Accessed 1/1/18
Sound Familiar?
“Recreational Genomics”What are the benefits and concerns about DTC genetic testing?
The Grand Idea & Appeal of DTCGT
• Affordable, accessible, and user-friendly• Testing privacy within your home• Learn surprising and fun information re: yourself • Extra information will increase patient engagement
• Potentially identify contributors to health risk early• Proactively change behaviors and habits • Proactively help your health care provider
Why not?Burke W et al. Ann Intern Med. 2016;164(8):564-565.
But buyer, beware.
Tempting and leading messaging
ORIG3N: Available at: https://orig3n.com/why-dna-tests/. Accessed 1/1/18
Technical Concerns of DTC Genetic Testing
Analytical validity• Accuracy of the test & the staff/laboratory running them
Clinical validity• Relevance of the test to disease
Clinical utility• Helpfulness of the test for disease diagnosis, management, prevention
Who’s selecting, performing, and interpreting the tests??
Genetics Home Reference. Available at: https://ghr.nlm.nih.gov/primer/testing/validtest. Accessed 1/1/18.
Well, someone must be regulating this, right?2006-2008: A Period of Investigation
• GAO investigation of online DTCGT companies • CDC, FDA, FTC consumer alerts
• Claims of benefit• Reliability and quality
• Recommendations• Specialized laboratory testing• Result interpretation by trained health care personnel
• Some states order DTC companies to obtain CLIA licenses
A Story of Fits and Starts
Summer 2010: Response to Expansion• Pathway Genomics + Walgreens announce partnership to sell OTC kits• FDA announces intent to regulate
• Medical devices? Potential legal action• Walgreens withdraws
• Congressional investigation into DTCGT companies1
• GAO releases damning investigation outcomes2
2013• 23andMe ordered to stop selling “health-risk” service3
1. US Government Printing Office. Available at: https://www.gpo.gov/fdsys/pkg/CHRG-111hhrg78125/pdf/CHRG-111hhrg78125.pdf. Accessed 1/22/182. Government Accountability Office. Available at: https://www.gao.gov/products/GAO-10-847T. Accessed 1/1/183. Food and Drug Administration. Available at: https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm376296.htm. Accessed 1/1/18
DTC Testing: Fits and Starts
“De novo premarket review pathway” • Pathway for future tests/companies• Expectations on test accuracy, reliability, clinical relevance• Not for diagnostic tests• Not for diagnosing or informing treatment decisions
FDA. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm551185.htm. Accessed 1/1/18.
DTC Testing: Fits and Starts
FDA. https://www.fda.gov/news-events/press-announcements/fda-authorizes-first-direct-consumer-test-detecting-genetic-variants-may-be-associated-medication. Accessed 7/30/19.
DTC Testing: Fits and Starts
FDA. https://www.fda.gov/medical-devices/safety-communications/fda-warns-against-use-many-genetic-tests-unapproved-claims-predict-patient-response-specific. Accessed 7/30/19.
DTC Testing: Fits and Starts
FDA. https://www.fda.gov/news-events/press-announcements/fda-issues-warning-letter-genomics-lab-illegally-marketing-genetic-test-claims-predict-patients. Accessed 7/30/19.
DTC Testing: Fits and Starts
360Dx. https://www.360dx.com/regulatory-news/inova-decides-end-pgx-test-offerings-response-fda-warning-letter. Accessed 7/31/19.
Driving a wedge?
Sharing test results• 63% planned to share results with a healthcare provider• 27% did
Inverse satisfaction with HCP after discussion• Knowledge• Willingness to discuss results• HCP willingness to incorporate results• Trust in HCP interpretation
Consistent trust in DTC testing company interpretation
van der Wouden et al. Ann Intern Med. 2016;164(8):513-522.
Consequences: Tales of a Google search• Whoops. How [company] Outed Parents Who Gave Their Baby Up For
Adoption.• [Company] has a problem when it comes to ancestry reports for people
of color• With genetic testing, I gave my parents the gift of divorce• How Reliable Are Home DNA Ancestry Tests? Investigation Uses Triplets
to Find Out• Patients less excited about DNA tests if insurers see results• [Company], which sold dubious DNA tests to predict addiction risk, sells
off assets as CEO departs amid criminal probe• Genetic testing firms filing for bankruptcy deprive CMS of hundreds of
millions
Consequences • Where? • Low-income housing, senior centers,
health fairs, antique shops• How?
• Cold calls, door knocking, email, Craigslist, social media ads
• Freebies: food, gift cards• Fear of terminal illness, memory
issues, trust• Prescriber kickbacks
• Outcome?• Medicare fraud• Unnecessary testing • Identity theft
NBC News. https://www.nbcnews.com/health/aging/genetic-testing-scam-targets-seniors-rips-medicare-n1037186. Accessed 7/31/19.
The Pharmacist’s Role
Aaron Bacall: “Here’s My DNA sequence”, 2000
The Pharmacist’s Role
American Society of Health-System Pharmacists (2014)• Leadership role • Ordering, reporting, and interpreting PGx tests• Design workflow processes• Research endeavors• All pharmacists should have basic understanding of PGx
Support from other healthcare disciplines (i.e., genetic counselors) for significant pharmacist role.
67
American Society of Health System Pharmacists. Am J Health-Syst Pharm. 2015; 72:579-81Mills et al. Pharmacogenomics. 2013;8:957-68
Pre-Test Counseling
What PGx testing can/can’t do• Clinical utility, benefits, limitations, risks• Potential benefit in improving medication management• Results may have lifelong relevance
Assess health literacy and previous exposure
Differences between types of testing• Disease risk (likelihood of contacting a particular disease)• Medication response (drug-gene interactions, changes in efficacy/adverse
effects)
68Zierhut et al. Pharmacotherapy. 2017;37(9):990-9.
Post-Test Counseling
Discuss test results & what they mean• Genotype to phenotype translation• Define terms used in testing• Everyone has variations in genetic code: more or less doesn’t mean good or
bad
Impact on medication selection• Doesn’t mean a currently effective medicine needs to be changed
Impact of non-genetic factors• Other health conditions drug-drug interactions, age, diet, exercise
69Zierhut et al. Pharmacotherapy. 2017;37(9):990-9.
Counseling: DTC Genetic Testing• Disease risk is multifactorial: Genetics is one component
• State of the industry• Relaxing regulation, but largely unregulated (test development and procedures)
• Nuances of test assumptions, interpretation, recommendations• Wide range of claims are made (many unverified, unproven) • Limited number of variants usually tested• Are the results really relevant to the individual patient?• What do “negative,” “normal,” “risk,” “likelihood” mean?• Are behavioral, diet, treatment recommendations evidence-based?• NOT diagnostic! – SHOULD NOT INFLUENCE DIAGNOSIS OR TREATMENT
Counseling: DTC Genetic Testing
• Discuss the relevance of DTC testing with HCPs• Understand the results and understand if they’re meaningful• Usefulness and limits• Benefits and risks
• Patient privacy/Data Use/Integrity• Read what you’re consenting to (present and future)• Attached strings (ex: research participation, what happens next?)• Consequences of partnerships, mergers/acquisitions, and collaboration • Hacking, law enforcement
• Pharmacy technicians First line triage of patient interest and behavior
Take-Home Points1. Precision health will advance person-specific management of individual
health, and pharmacists will increasingly encounter pharmacogenetics-related questions in the future.
2. CPIC and PharmGKB are evidence-based resources to help interpret pharmacogenetic test results.
3. Although DTC genetic testing is increasingly accessible, it is largely unregulated, risks are involved, the claims can be questionable, and results can be easily misinterpreted.
4. Genetic testing is not a crystal ball. Other clinical factors must be considered.
5. All pharmacists must maintain a basic understanding of PGx to appropriately provide recommendations for drug therapy and guide patients on the utility of genetic testing.
Interested in more?Certificate Programs
• American Society of Health-System Pharmacists• University of Colorado
Graduate Degree Programs• University of Florida• Manchester University
Conferences• Professional meetings• University of Florida Precision Medicine Conference
Online resources• Genetics/Genomics Competency Center (G2C2) – genomicseducation.net• Clinical Pharmacogenetics Implementation Consortium (CPIC) – cpicpgx.org• National Institutes of Health Genetics Home Reference – ghr.nlm.nih.gov • PharmGKB – pharmgkb.org
Post-graduate training• PGY-2 residency• Fellowship