Pharmacogenomics

Resources
Dr Yassin Khaled
Learning Outcomes
• Identify various pharmacogenomics resources.
• Describe the role of the various pharmacogenomics resources
• Apply appropriate pharmacogenomics resources to clinical cases
• Discuss sections of the CPIC® guidelines and their relevance to
practice
• Describe major pharmacogenomics guideline writing groups
Introduction
• Implementation of pharmacogenetics in clinical practice has been
relatively slow despite substantial scientific progress in understanding
linkages between genetic variation and variability of drug response and
effect.
• One factor that has inhibited the adoption of genetic data to guide
medication use is a lack of knowledge of how to translate genetic test
results into clinical action based on currently available evidence
• Fortunately, there are many freely available, evidence-based resources
that clinicians can reference when faced with these challenges.
• Clinical practice guidelines exist that provide clinicians with actionable
prescribing recommendations based on genetics
What is CPIC®?
• Clinical Pharmacogenetics Implementation Consortium (CPIC®) was
established in 2009
• Goals of CPIC® :
• – Accelerate implementation of research discoveries in PGx into the clinic
• – Address some of the barriers to implementation of PGx tests into clinical
practice
• Goals are accomplished by:
• – Creating and providing freely available, peer-reviewed, updatable, and
detailed gene/drug PGx clinical practice guidelines
• www.cpicpgx.org
ASSUMPTION OF CPIC® GUIDELINES
• CPIC guidelines are designed to help clinicians understand HOW
available genetic test results should be used to optimize drug therapy
• – Not WHETHER tests should be ordered
• Key assumption:
• – Clinical high-throughput and preemptive genotyping will become
more widespread
• – Clinicians will be faced with having patients’ genotypes available
even if they did not order test with drug in mind
CPIC® MEMBERSHIP COMPOSITION
• As of October 2020:
• > 400 members
• Clinicians and scientists
• > 260 institutions
• 35 countries
• 14 observers (NIH, FDA, professional societies)
• – CPIC® Informatics
• > 35 members from 25 organizations
MAIN TABLES IN CPIC® GUIDELINES
• Table 1: diplotype to phenotype translation
• Table 2: prescribing recommendations linked to phenotypes,
standard grading for strength of recommendation
• Supplementary materials:
• – Allele definition table
• – Allele functionality table
• – Gene frequency tables
• – Diplotype-phenotype assignment table
• – Informatics related resources

https://www.youtube.com/watch?v=aEZPu1rqHic
GRADING STRENGTH OF RECOMMENDATION
DUTCH PHARMACOGENETICS WORKING GROUP

https://www.knmp.nl/producten/gebruiksrechtgstandaard/informatieoverdegstandaard/
thegstandaardthemedicinesstandardinhealthcare

Also available at
www.pharmgkb.org
DPWG PROVIDES A SINGLE GUIDELINE WITH ALL
RECOMMENDATIONS
• DPWG founded by the Royal Dutch Association for Advancement of
Pharmacy
• Provides dosing recommendations for 53 drugs and 11 genes in one single
guideline
• Gene/drug list mostly similar to CPIC® guidelines
• Gene/drug specific recommendations can also be found on the PharmGKB
website
Assignment 1

• Visit the CPIC Website: https://cpicpgx.org/. Select and review a gene drug guideline.
Briefly describe how these recommendations may be applied to clinical practice. This
activity is intended to build your experience with accessing pharmacogenomic guidelines
and how they may be integrated into prescribing decisions.
• Please select a gene drug guideline and fill the following information accordingly.
• Gene
• Drug
• CPIC level
• Pharm GKB level of Evidence
• PGx on FDA Label
• Summary of the guidelines
 Beyond the Guidelines:
Additional Resources for Clinical Pharmacogenomics
Key PGx Resources
• There are many resources to help answer clinical pharmacogenomic
resources beyond CPIC guidelines
• When faced with a pharmacogenomics clinical question or implementation
challenge, understanding the nature and scope of these diverse resources
will be an asset.
• Leveraging these key resources will facilitate the appropriate use of
pharmacogenomic data in patient care.
• You must develop a structured way to answer pharmacogenomic based
questions.
• Build off of what others have previous done
PHARMGKB
• Pharmacogenomics knowledge resource that encompasses clinical information
including dosing guidelines and drug labels, potentially clinically actionable gene-
drug associations and genotype-phenotype relationships.
• Search by:
• Drug
• Gene
• Variant
• Contains
• – Guidelines
• – Drug label wording
• – Clinical and variant annotations
• – Pathways
• – Very Important Pharmacogenes (VIPs) summary
PHARMGKB - GUIDELINES

• Organized by drug
• Guidelines covered
• – CPIC®
• – DPWG
• – CPNDS
• – Others e.g. practice specific professional organizations
• Videos on some CPIC® guidelines
PHARMGKB – Drug Label
• Organized by drug
• Authorities covered
• – FDA
• – EMA
• – HCSC
• – PMDA
• – Swissmedic
• PGx levels
• – Testing required
• – Testing recommended
• – Actionable PGx
• – Informative PGx
PHARMGKB - ANNOTATIONS

• Clinical annotations
• – Variant annotations
• Phenotype for any given genotype is reported relative to the other
genotypes
• – Strength of evidence
• – Level 1A: CPIC® or medical society-endorsed PGx guideline
• – Level 1B: preponderance of evidence shows an association
• – Level 2A: qualifies for level 2B where the variant is within a Very Important
Pharmacogenes
• – Level 2B: moderate evidence of an association
• – Level 3: single significant not yet replicated study or multiple studies but lacking
clear evidence of an association
• – Level 4: case report, non-significant study or in vitro, molecular or functional assay
evidence only
EXAMPLE
PHARMGKB - ANNOTATIONS
PHARMGKB - VERY IMPORTANT
PHARMACOGENE & PATHWAYS
• Very Important Pharmacogenes summary
• – Overview of a significant gene involved in metabolism of or response
to one or several drugs
• Pathways
• – Evidence-based diagrams of drugs with pharmacogenetic
associations
• Pharmacokinetics
• Pharmacodynamics
PHARMGKB - GENE-SPECIFIC TABLES
• Allele definitions
• – Translation tables
• Allele functionality
• Frequency tables
• – Allele
• – Diplotype
• – Phenotype
• Diplotype-phenotype
• Gene resource mapping
TRANSLATION TABLE

???
Assignment 2

• Visit the website for the PharmGKB https://pharmgkb.org

• browse the section of drug label annotations for any drug and fill in
the following data:
• Drug label annotations
• Clinical annotations
• Variant annotations
• Pathways (briefly)
PHARMACOGENE VARIATION
(PHARMVAR) CONSORTIUM
• Home for PGx gene nomenclature serving as a centralized
‘Next-Generation’ Pharmacogene Variation data repository
• – Official and unified allele designation system for the global PGx
community
• Organized by gene
• – Star alleles haplotypes
• – Variants
• Links to rsID and dbSNP
• – Functional assignments
• – References
DBSNP
• Central repository for both single base nucleotide substitutions
and short deletion and insertion polymorphisms
• – National Human Genome Research Institute and National Center for
Biotechnology Information collaboration
• Indexed by rsID
• – MAF (minor allele frequency)
• Reference populations
• – HGVS names
• – ClinVar annotations
• – Gene structure
GENETIC TESTING REGISTRY
• Central location for voluntary submission of genetic test information
by providers
• – Purpose
• – Methodology
• – Validity
• – Evidence of the test's usefulness
• – Laboratory contacts
• – Credentials
• Search by
• – Tests
• – Genes
• – Condition
• – Lab
Gene Reviews (for non pharmacogenes)
• Resource for clinically relevant and medically actionable information for
inherited conditions
• – Diagnosis
• – Management
• – Genetic counseling for patients and their families
• Search by
• – Gene
• APOE
• – Phenotype
• 1p36 Deletion Syndrome
• – Common condition
• Alzheimer
FDA BIOMARKER LIST

• Over 100 drugs

• Somatic
• – ERBB2
• Pharmacogenes
• – CYP2D6
• Other germline gene
• – POLG
• Identifies section in label
• READ LABEL INFORMATION CAREFULLY
• – Actionable
• – Informative
Assignment 3
• Visit the website for the FDA Table of Pharmacogenomic Biomarkers
at https://www.fda.gov/drugs/science-and-research-drugs/table-
pharmacogenomic-biomarkers-drug-labeling
• Choose any drug and identify their pharmacogenomic information
found in the drug labeling sections.
• Drug:
• Therapeutic area:
• Gene/biomarker:
• Details of labeling sections including PGx information:
 FDA TABLES OF PHARMACOGENETIC ASSOCIATIONS
Drug-gene pairs that the FDA has
evaluated and considers to possess
sufficient evidence
• Inclusion in the table:
– Does NOT mean the FDA advocates
for a specific
test before prescribing
– NOT an exhaustive list
– Open for comment from the
community
Multiple tables are available
– Support Therapeutic management
recommendations
• 51 drug-gene pairs
– Potential impact on safety or
response
• 19 drug-gene pairs
– Pharmacokinetic associations only
• 37 drug-gene pairs
STEPS TO ANSWER A PGx QUESTION
• Are there guidelines or consensus statements regarding this gene?
• How will this testing result in improved patient care over current clinical
practice?
• What is the prevalence of the gene variants in the population?
• What is the availability, cost, and reliability of clinical testing?
• What is the expected time to return of test results?
– Does this fit within appropriate clinical window?
• What are the related clinical trials, outcomes/translation studies?
• What would be the therapeutic recommendation?
– Do they raise pharmacogenomic concerns?
• Is the gene or variants related to non pharmacogenomic conditions?
• Are there ethical, legal, and social implications?
WHERE TO FIND THE ANSWERS?
• Are there guidelines or consensus statements regarding this gene? PharmGKB
• How will this testing result in improved patient care over current clinical practice?
PharmGKB, PharmVar, FDA websites, and PubMed
• What is the prevalence of the gene variants in the population? dbSNP
• What is the availability, cost, and reliability of clinical testing? Genetic Test Registry and
PharmVar
• What is the expected time to return of test results? Genetic Test Registry
• What are the related clinical trials, outcomes/translation studies? PharmGKB, FDA
websites, and Pubmed
• What would be the therapeutic recommendation? PharmGKB and FDA websites
• Is the gene or variants related to non pharmacogenomic conditions? GeneReviews
• Are there ethical, legal and social implications? GeneReviews
Thank you