BeyondtheHype:Developing, Implementing,andSharing PharmacogenomicClinical DecisionSupport

PanelOverview
Clinicaldecisionsupport(CDS)inthe electronichealthrecord(EHR)willplaya crucialroleinmaximizingtheuseof pharmacogenomicdataoverapatients lifetime. Lessonslearnedatinnovatorsitesmustbe organizedandsharedamongcaresettingsand EHRvendors

Objectives
Compareandcontrastearlyadopters approachtodevelopandimplementCDSfor pharmacogenomics. ReviewtheroleoftheEHRandCDSin facilitatingthetestingapanelofdrug metabolismgenesamongappropriatepatient populations.

Objectives
ReviewtheuseofactiveandpassiveCDSfor pharmacogenomicsatinnovatorsites, includingdrug/genepairsinuseand frequencyofuse. Identifychallengesandbarrierstodeveloping andimplementingCDSfor pharmacogenomics. DescribestrategiesforsharingCDSacrosscare settingsandEHRplatforms.

Speakers
1. JoshF.Peterson,MD,MPH
VanderbiltUniversitySchoolofMedicine,NashvilleTN

2. JamesM.Hoffman,PharmD,MS
St.JudeChildrensResearchHospital,Memphis,TN

3. RobertR.Freimuth,PhD
MayoClinic,Rochester,MN

4. MarkHoffman,PhD
CernerCorporation,KansasCity,MO
BriefQuestionsaftereachpresenterandpaneldiscussionattheend

BeyondtheHype: Developing,Implementing,andSharing PharmacogenomicClinicalDecisionSupport

AMIASummitonTranslationalBioinformatics
March18,2013
JamesM.Hoffman,Pharm.D.M.S. AssociateMember,PharmaceuticalSciences St.JudeChildrensResearchHospitaland PAAR4Kids,NIHPharmacogenomicsResearchNetwork

Objectives
Identifystepsandresourcesfordevelopment andimplementationofpharmacogenomic CDS Describekeydesignchoicesofpassiveand activepharmacogenomicCDSatSt.Jude Identifyopportunitiestofacilitatebroader adoptionofpharmacogenomicCDS

ASimplifiedModelofCDS Implementation
Evaluation Governance, Design,and Knowledge Base Implementation

Discovery

Forpharmacogenomics,establish GenotypingApproachtoprovidedatafor eachpatient

Asuseofpharmacogenomicsexpands, howcanweacceleratetheprocess?

DevelopmentandImplementationof PharmacogenomicCDSat

FDAasaknowledgebasefor pharmacogenomicsandCDS
FDAmaintainsatabledrugswith pharmacogenomic informationintheirlabels
Over115drugsintableasofFeb2013!

FDAusespharmacogenomicswhenevaluating andcommunicatingdrugsafety
Codeineprominentcurrentexample

http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.ht m

 CPICsInherentframework:
Ifyouhadthegenotyperesult,howshould youactonit?

Consistentwithpreemptive,arraybased genotyping CPICincludes

Over60cliniciansandscientists,from
33institutions 12countries

ObserversfromNIHandFDA

http://beta.web.st jude.org/news/rel ling/jl3404_PGEN 4Kids.html

St.JudeFamilyAdvisoryCouncil(AliciaHuetteletal)
Greatdiversityofopinion
FromwhyareyoutellingmethistoIwantto decidewhenthisgoesinrecord

Highlevelofinterest HelpedtoputtogethereducationalDVD Remainengagedinprotocol

PharmacogeneticsOversight CommitteeatSt.Jude
Representativesfromacrossthehospital Meetsquarterly Approves
Gene/drugpairsforimplementation decisionsupportmessagesandmechanisms

ReportstoPharmacyandTherapeutics Committee

TimelineforClinicalGenotypingandCDSatSt.Jude
SOME ActiveCDS Comprehensive Passiveand ActiveCDS

2000

2007

2009

2011

Crewsetal.Amer JHealthSyst Pharm 2011;68(2):14350.

AbilitytogenotypeatlotsoflocionCLIA approvedarrayiscoming hereandallowsfor preemptivegenotyping AffyDMETarray:over1millionfeaturesto interrogate1900polymorphismsin225genes

Outstandingconcordancewithorthogonal methodsofgenotyping(Fernandezetal,CPT, 2012)

Forthesamemoneywespendon2genes,we caninterrogate225genes
Makespreemptivegenotypingapossibility

PG4KDS :CLINICALIMPLEMENTATION

OFPHARMACOGENETICSatST.JUDE
18 months May 20th 2011 to Jan 30th, 2013 Goal: migrateCurrent pharmacogenetic testsfrom First pt enrolled clinic n laboratory (array based) intoroutinepatient 08Jun2011 Neuro oncology 165 10care, Jun2011 BMT tobe availablepreemptively 20 04May2012 Aftercompletiontx 4 21May2012 HIV 92 24Apr2012 Radiationoncology 29 24Jun2011 Solid tumor 189 27May2011 Leukemia 277 08Nov2012 NonmaligHematology 180 Total 956

BothpassiveandactiveCDSare essentialforpharmacogenomics
Keydesigndecisionsmadeduringdevelopmentand implementation: PassiveCDS Concisegenespecific interpretationsmustbe providedtoclinicians throughtheEHR Theinformationwillbe postedoncepergene Manycombinationsexist, andsotheprocessmustbe automated ActiveCDS Preandposttestalerts Highriskphenotypes automaticallyplacedonthe problemlist Interruptivepointofcarealert triggeredwhenproblemlist entryandhighriskdrug prescribingcombine Drugspecificinformation provided

CYP2D6 LookupReferenceTable DiplotypeLinkedtoPriorityandPhenotype

DiplotypeinMilli(Result) (*5/*5)0N (*1/*1)1N (*2/*2)1N (*1/*1,*1/*9,*9/*9)1N (*41/*41)1N (*17/*17,*17/*40,*40/*40)1N (*4/*4)1N (*1/*1)2N (*1/*10)2N (*1/*17)2N (*1/*2)3N (*1/*3)2N (*1/*41)2N (*1/*6)2N Phenotype PM EM EM EMorIM IM IMorPM PM EM EM EM UM EM EM EM Priority EMRFlag(Color) Priority Abnormal Routine Normal Routine Normal Routine Normal Routine Normal Indeterminate Abnormal Priority Abnormal Routine Normal Routine Normal Routine Normal Priority Abnormal Routine Normal Routine Normal Routine Normal

PharmacogeneticstabaddedtoEMR; allclinicallyeligiblegenotypesareentered, alongwithagenespecificconsultandlettertopatient

***PHARMACOGENETICS CONSULT FOR*** *CYP2D6 GENOTYPE* Sample for CYP2D6 Genotype Obtained: 9/22/2011 PG4KDS CYP2D6 Genotype Result: (*1/*1)2N Based on the genotype result this patient is predicted to be an extensive (normal) metabolizer of CYP2D6 substrates. This result signifies that the patient has two copies of a wild-type (normal function) allele. The expected phenotype suggests that there is no reason to selectively adjust the dose of most medications (including codeine) that are metabolized by the CYP2D6 enzyme pathway. The diplotype result equates to a CYP2D6 activity score of 2. For more information about specific medications metabolized by CYP2D6, please go to www.stjude.org/pg4kds. Comments: none Jane Smith, Pharm.D., pager 1234

Deconstruct the consult into sections; scalable to add additional diplotypes

Phenotype Assignment (6 versions) Diplotype Interpretation (32 versions) Dosing Recommendations (6 versions) Activity Score (11 versions) Educational Link

Hicksetal(CPT2012)

TPMTPrepharmacogenetictestwarning:at pointofcaretoprescriber

Highriskdiplotypestranslatedto phenotype,automaticallypopulated intoProblemListofEMR

Why use the problem list?
- Experience
Useful when building other active CDS

- Flexible
Incorporate outside result Emerging drug information Can incorporate other data (e.g. dose)

- Scalable and generalizable to others

Posttest:whenahighriskdrugcollideswithahighrisk(priority) genotype,activeCDSalertsfireatpointofcare

35customdrugandphenotype specificrulesimplemented:
TPMTwiththiopurines (azathioprine,thioguanine,and mercaptopurine) CYP2D6 withvariousdrugs(codeine,tramadol, amitriptyline,fluoxetine,andparoxetine)
Patients with high-risk genotype: e.g. CYP2D6 UM or PM; CYP2C19 PM; TPMT heterozygote Patients with high-risk drugs: e.g. codeine, amitriptyline; clopidogrel azathioprine

Ifahighriskdrugisorderedforapatientwitha highriskgenotype,MDgetsawarningintheEHR

Standardsneeded fordiagnosticterms
TPMT SNOMED CT Code
Thiopurine methyltransferase deficiency PROGRESS FromLOINC!!! vs

TPMT- St Jude EMR Terms

TPMT TPMT TPMT TPMT Normal Activity Intermediate Activity Possible Intermediate Activity Low or absent Activity

Suggestionsforsuccessful pharmacogenomicCDS
UseknowledgebasessuchasCPICprovide clinicalcontent DevelopbothpassiveandactiveCDS
PretestandposttestactiveCDSmaybeneeded

Remainmindfuloftheriskforalertfatigue
Posttestalertsinterruptcliniciansonlywhena highriskdrugisorderedonapatientwithahigh riskphenotypeontheproblemlist

ActiveCDScanbebasedontheproblemlist

SJPharmaceutical KrisCrews KevinHicks GillianBell ChristianFernandez CyrineHaidar ShaneCross JamesHoffman NancyKornegay PamMcGill EmilyMelton AlejandroMolinelli ColtonSmith WilliamEvans MarkWilkinson WenjianYang

Kelly Caudle PaulaCondy LisaWalters TerriKuehner SheriRing ShannonGibbs MargaretEdwards SJBiostatistics ChengCheng DeqingPei MCW Uli Broeckel Rachel Lorier Alexander Stoddard

St.Jude ScottHoward JerryShenep ChingHonPui AlbertoPappo SimaJeha AdityaGaur UlrikeReiss AliciaHuettel MelissaHudson AmarGajjar InformationSciences DonBaker Keith Kunkel AndrasSablauer RajeshParashuran DavidZhao

PGRN
JoshPeterson TeriKlein AlanShuldiner JulieJohnson Russ Altman DickWeinshilboum Wolfgang Sadee DanRoden