Implementing Pharmacogenomics in Europe: Design and Implementation Strategy … · 2017. 4. 11. ·...
Transcript of Implementing Pharmacogenomics in Europe: Design and Implementation Strategy … · 2017. 4. 11. ·...
-
Implementing Pharmacogenomics in Europe:Design and Implementation Strategy of theUbiquitous Pharmacogenomics ConsortiumCH van der Wouden1, A Cambon-Thomsen2, E Cecchin3, KC Cheung4, CL D�avila-Fajardo5, VH Deneer6,V Dol�zan7, M Ingelman-Sundberg8, S J€onsson9, MO Karlsson9, M Kriek10, C Mitropoulou11,GP Patrinos12, M Pirmohamed13, M Samwald14, E Schaeffeler15, M Schwab15,16,17, D Steinberger18,J Stingl19, G Sunder-Plassmann20, G Toffoli3, RM Turner13, MH van Rhenen4, JJ Swen1, andH-J Guchelaar1 on behalf of the Ubiquitous Pharmacogenomics Consortium
Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remainslimited. Opportunely, several implementation studies and programs have been initiated over recent years. This articlepresents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undeterminedcollective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currentlylimited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has beenfunded by the European Commission’s Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions[PREPARE]), pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will beimplemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multi-healthcare system approach.
Pharmacogenomics in precision medicinePharmacogenomics (PGx) informed prescribing is one of the firstapplications of genomics in medicine.1,2 It promises to personalize
medicine by using an individual’s genetic makeup, which predictsdrug response, to guide optimal drug and dose selection.3,4 Thisremoves the traditional “trial and error” approach of drug
*Members of the Ubiquitous Pharmacogenomics Consortium at the time of publication: J. Antolinos-P�erez, A. Balasopoulou, K. Blagec, A. Cambon-Thomsen, E.Cecchin, K. Chalikiopoulou, K.-C. Cheung, C.L. D�avila-Fajardo, V.H. Deneer, V. Dolzan, M. Dupui, P. Franssen, L. Grandia, H.-J. Guchelaar, A. Hanson, S. Hofer,I. Holsappel, M. Ingelman-Sundberg, W. Jama, S. J€onsson, K. Just, M.O. Karlsson, T. Katsila, J. Klen, R. Koopmann, M. Kriek, V.M. Lauschke, S. L�opez-Fern�andez, E. Mendrinou, C. Mitropoulou, G. Mlin�sek, R. Moreno-Aguilar, M. Nijenhuis, Å. Nordling, G.P. Patrinos, C. Pavlidis, M. Pirmohamed, A. Poplas Susič,E. Rial-Sebbag, V. Rollinson, L. Rook, M. Samwald, J.G. S�anchez-Ramos, E. Schaeffeler, A. Schmidt, M. Schwab, G. Sengoelge, M. Steffens, D. Steinberger, J.Stingl, G. Sunder-Plassmann, J.J. Swen, G. Toffoli, P. Toledo-Fr�ıas, R. Tremmel, E.-E. Tsermpini, R. Turner, M. van der Lee, J.-G. Wojtyniak, C.H. van derWouden, M.H. van Rhenen, and H. Xu.1Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands; 2UMR Inserm U1027 and Universit�e de ToulouseIII Paul Sabatier, Toulouse, France; 3Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico, National Cancer Institute, Aviano, Italy; 4RoyalDutch Pharmacists Association (KNMP), The Hague, The Netherlands; 5Department of Clinical Pharmacy, Granada University Hospital, Institute for BiomedicalResearch, Granada, Spain; 6Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands; 7Pharmacogenetics Laboratory, Institute ofBiochemistry, Faculty of Medicine, University of Ljubljana, Slovenia; 8Department of Physiology and Pharmacology, Section of Pharmacogenetics, KarolinskaInstitutet, Stockholm, Sweden; 9Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; 10Center for Clinical Genetics, LeidenUniversity Medical Center, Leiden, The Netherlands; 11The Golden Helix Foundation, London, United Kingdom; 12University of Patras, School of HealthSciences, Department of Pharmacy, University Campus, Rion, Patras, Greece; 13Department of Molecular and Clinical Pharmacology, Royal Liverpool UniversityHospital and University of Liverpool, Liverpool, United Kingdom; 14Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University ofVienna, Vienna, Austria; 15Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of T€ubingen, T€ubingen, Germany;16Department of Clinical Pharmacology, University Hospital T€ubingen, T€ubingen, Germany; 17Department of Pharmacy and Biochemistry, University of T€ubingen,T€ubingen, Germany; 18Bio.logis Center for Human Genetics, Frankfurt am Main, Germany; 19Research Division, Federal Institute for Drugs and Medical Devices,Bonn, Germany; 20Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. Correspondence: H-JGuchelaar ([email protected])
Received 31 October 2016; accepted 13 December 2016; advance online publication 27 December 2016. doi:10.1002/cpt.602
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 3 | MARCH 2017 341
-
prescribing, thereby promising safer, more effective, and cost-effective drug treatment.5,6 The discrepancy between germline andsomatic PGx is of importance with regard to PGx clinical imple-mentation.7 Despite significant progress in the field of somaticprecision medicine, it is outside the scope of this review. Severalrandomized controlled trials have provided gold-standard evidencefor the clinical utility of single drug-gene PGx tests to: (1) guidedosing for warfarin,8,9 acenocoumarol, phencopromon,10 and thi-opurines11; and (2) guide the drug selection of abacavir.12 Addi-tionally, several prospective cohort studies have been performedindicating the clinical utility of single drug-gene PGx tests to guidedrug selection of carbamazepine13 and allopurinol.14 However,many argue that the perceived mandatory requirement for pro-spective evidence to support the clinical validity of a PGx test, pri-or to its implementation into routine care, is incongruous andexcessive.15–18 The notion of “genetic exceptionalism” has beenheld responsible.19 Several recent studies estimate that 95% of thepopulation carry at least one actionable genotype.20,21 Becauseactionable PGx variants are ubiquitous and germline PGx resultsare life-long, we consider that quantifying the collective clinicalutility of a panel of PGx-markers to be more relevant than provid-ing evidence for individual drug-gene pairs. However, this will stillrequire the systematic implementation of a pre-emptive PGx strat-egy across multiple drugs, genes, and ethnicities, and the robustassessment of this intervention impacts on both individual patientcare and healthcare service processes. It is our expectation that thegeneration of such evidence will support the population-wideimplementation of pre-emptive PGx testing.
Barriers preventing pharmacogenomics implementationThere have been advances in PGx implementation, but signifi-cant barriers remain, including those preventing clinical imple-mentation.22–26 The remaining hurdles include improvingphysician and pharmacist awareness and education aboutPGx,27,28 the development of tools to implement PGx resultsinto the workflow of physicians and pharmacists,29,30 and theundecided reimbursement of PGx tests. Finally, and most impor-tantly, evidence presenting the collective clinical utility of a panelof PGx-markers remains to be established. It is envisaged that sur-passing these daunting barriers will provide the impetus for thewidespread adoption of both the Dutch PharmacogenomicsWorking Group (DPWG) guidelines31,32 and the Clinical Phar-macogenetics Implementation Consortium (CPIC) guide-lines,33–46 which will help to realize the potential of PGx.
Current implementation projects are addressing these barriersSeveral of the documented hurdles obstructing the implementa-tion of PGx are currently being addressed by various initiatives,both in the United States and the European Union. A compactoverview of these initiatives is provided in the following sections.From this overview, both trends and remaining research gapshave been identified. Various initiatives attempt to increase physi-cian and pharmacist knowledge of PGx, and a diverse range oftools have been developed to integrate PGx testing results intotheir workflow. However, a significant research gap, whichremains unmet, is the absence of evidence presenting the
collective clinical utility of a panel of PGx-markers. The Ubiqui-tous Pharmacogenomics Consortium (U-PGx), therefore, aims toprovide this evidence in a large-scale, multidrug, multigene, multi-center, multi-ethnic approach to PGx testing.
The Ubiquitous Pharmacogenomics ConsortiumThe U-PGx Consortium is an established network of Europeanexperts equipped to address the remaining challenges andobstacles for clinical implementation of PGx into patient care.16
Funded by a 15 million Euro Horizon 2020 grant from the Euro-pean Commission, the U-PGx Consortium aims to make action-able PGx data and effective treatment optimization accessible toevery European citizen. The U-PGx Consortium will investigatethe impact on adverse event incidence and healthcare costs fol-lowing the widespread implementation of pre-emptive PGx test-ing using a panel of clinically relevant markers. As opposed tomany other implementation initiatives, U-PGx will implementPGx through a pre-emptive panel strategy as opposed to imple-menting an individual drug-gene pair. For reasons stated above,this approach is designed to provide relevant evidence supportingthe implementation of PGx in routine care. U-PGx uses a multi-faceted approach consisting of four components to achieve thisobjective, as shown in Figure 1, and members of each componentare mapped in Figure 2. The first component focuses on develop-ing the enabling tools necessary to integrate PGx test results intothe electronic health record (EHR) and clinical decision supportsystem (CDSS), taking into account the differences in health caremodels, languages, and laws across the European Union. Theseenabling tools consist of information technology solutions, PGxtesting infrastructure, educating healthcare professionals in PGx,and translating the existing DPWG guidelines, which wereupdated only in the Dutch language, to six other local languages.This component will pave the way for the unobstructed opera-tion of component two. This second component will implementpre-emptive genotyping of a panel of 50 variants in 13 pharmaco-genes into clinical practice, in the context of a large prospective,international, block-randomized, controlled study (n 5 8,100).This study is called the PREemptive Pharmacogenomic testingfor prevention of Adverse drug REactions (PREPARE) study.Primarily, the study aims to assess the impact of PGx implemen-tation on adverse event incidence. Additional outcomes includecost-effectiveness, process indicators for implementation, andprovider adoption of PGx. A third component applies innovativemethodologies, such as next-generation sequencing (NGS), phar-macokinetic modeling, and systems pharmacology to discoveradditional variants associated with drug response and to elucidatedrug-drug-gene interactions. The final, fourth, component willfocus on ethical issues of the project and implications for PGx,and spearheads outreach and educational activities to influentialstakeholders. In comparison to the United States, projects withinthe European Union likely encounter even more challenges toachieve implementation because of the multilinguistic settings,different legal environments, and heterogeneous healthcare sys-tems of EU countries. The specific approaches adopted by thesecomponents and the design of the PREPARE study are furtherelaborated in the following sections.
342 VOLUME 101 NUMBER 3 | MARCH 2017 | www.cpt-journal.com
-
Figure 2 The established expert network of the Ubiquitous Pharmacogenomics (U-PGx) Consortium. The U-PGx Consortium consists of four components: (1)enabling tools; (2) the PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions (PREPARE) study; (3) a next step into the future; and (4)dissemination, communication, and ethical, legal, and societal impact (ELSI). The institutes listed above are members of the corresponding component.
Figure 1 An overview of the Ubiquitous Pharmacogenomics (U-PGx) Project. First, tools to enable the integration of pharmacogenomics (PGx) results intothe clinical decision support system will be developed, the Dutch Pharmacogenomics Working Group (DPWG) guidelines will be translated, and participatingphysicians and pharmacists will be educated in understanding and applying PGx during prescription and dispensing. Following this, the PREemptive Pharma-cogenomic testing for prevention of Adverse drug REactions (PREPARE) study will evaluate the impact of PGx implementation on clinical outcomes, cost-effectiveness, and implementation process metrics. The PREPARE study will provide data collection for innovative projects, which aims to expand ourunderstanding of PGx through next-generation sequencing and a systems pharmacology approach. In parallel, the final component supports the ethical pro-ceeding of the project and spearheads outreaching and educational activities to influential stakeholders. ELSI, ethical, legal, and societal impact; ICT, infor-mation communication technology; PGx, pharmacogenomics.
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 3 | MARCH 2017 343
-
OVERVIEW OF CURRENT IMPLEMENTATION STUDIESSeveral implementation studies have been initiated in the UnitedStates since 2010. An overview of published initiatives is given inTable 1.21,30,47–65 Additional, unpublished, initiatives may existoutside the scope of this table. A subsection of these studies haspreviously been summarized elsewhere.20 In the following sec-tions, the objectives and implementation strategies of these clini-cal implementation studies and programs are summarized.
Cleveland Clinic’s Personalized Medication ProgramThe Cleveland Clinic established the Center for PersonalizedHealthcare in 2011 to incorporate unique patient characteristics,including genetics, into the medical decision-making process. Thecenter has developed two programs, one of which is the Personal-ized Medication Program. This program was launched in 2012and aims to identify drug-gene pairs ready for integration intoclinical practice and developing the tools needed to implementinto the clinical workflow. The program has currently imple-mented HLA-B*1502-abacavir and TPMT-thiopurines into theclinical workflow and aims to implement two additional drug-gene pairs per year. An oversight committee selected these drug-gene pairs. Alerts and custom rules have been developed in theEHR to provide clinicians with point-of-care PGx decision sup-port. A clinical pharmacogenomics specialist provides support forboth patients and clinicians who require help with understandingthe PGx results. Future goals also include development of analgorithm that identifies patients who are at high-risk of receivinga drug for which pre-emptive genotyping would be useful.
CLIPMERGE pharmacogenomicsAs part of the Electronic Medical Records and Genomics(eMERGE)-PGx project, the Icahn School of Medicine at MountSinai has initiated the CLIPMERGE PGx Project for implement-ing PGx testing into the EHR and CDSS by using a biobank-derived cohort from the BioMe Biobank. Patients enrolled in thebiobank, who are likely to receive a drug with genetic interactionsand receive primary care at Mount Sinai Internal Medicine Asso-ciates, are eligible for inclusion. The 1,500 pilot patients are beingpre-emptively genotyped for known variants associated with drugresponse. CLIPMERGE-PGx aims to provide valuable insightinto the mechanisms, tools, and processes that will best supportthe use of PGx in clinical care. The investigators argue that beforepersonalized medicine can be realized, tools and best practices tofacilitate the delivery of PGx must be developed and evaluated sothat the question of utility can be answered without the burdenof a questionable process.48 As an initial result, a study amongincluded physicians suggested they have a deficit in their familiar-ity and comfort in interpreting and using PGx.49
Electronic Medical Records and GenomicsNetwork-PharmacogenomicsThe eMERGE-PGx is a partnership of the Electronic MedicalRecords and Genomics Network50 and the PharmacogenomicsResearch Network (PGRN).51,52 The eMERGE-PGx is a multi-center project that aims to implement targeted sequencing of 84pharmacogenes and assess process and clinical outcomes of this
implementation at 10 academic medical centers across the Unit-ed States. The goals of eMERGE-PGx are threefold: (1) to installan NGS sequencing platform to assess sequence variation in9,000 patients likely to be prescribed a drug of interest in a 1–3-year timeframe across the 10 clinical sites; (2) to integrate clinicallyvalidated genotypes into the EHR and CDSS and to measurethe resulting clinical outcomes and assess the implementationprocess; and (3) to develop a repository of variants of unknownsignificance linked to clinical phenotype data to expand PGxunderstanding.66
Implementing Genomics in PracticeImplementing Genomics in Practice (IGNITE) is a network ofsix sites and a coordinating center that aims to develop methodsfor, and evaluate the feasibility of, incorporating individualpatient’s genomic information into their clinical care. The net-work was established in 2013 and supports the development andinvestigation of genomic practice models, which are integratedinto the EHRs to inform decision-making at the point-of-care.Three of these sites focus on implementing PGx testing in clini-cal care: Indiana University (INGENIOUS), University of Flori-da (Personalized Medicine Program), Vanderbilt University(I3P).53
INdiana GENomics Implementation: an Opportunity for theUnderServedIndiana University School of Medicine and the Indiana Universi-ty Institute of Personalized Medicine, in collaboration with theEskenazi Health System, are conducting an NIH funded trial,which started recruitment in March 2015. INdiana GENomicsImplementation: an Opportunity for the UnderServed (INGE-NIOUS) implements pre-emptive PGx genotyping of a panel ofpharmacogenes through a randomized clinical trial. INGE-NIOUS is prospectively enrolling 6,000 patients, with 2,000patients assigned to the PGx testing arm and 4,000 to the controlarm. Both arms will be followed for a year after being prescribeda targeted medication. Open array genotyping will assess 43 var-iants in 14 genes known to affect the response of 28 drugs. Pri-mary outcomes include adverse event incidence and annualhealthcare cost. PGx results are integrated in the EHR andCDSS. Additionally, participating physicians are supported withprovided consultations in using the PGx results in routinecare.54,55
Personalized Medicine ProgramThe University of Florida and Shands Hospital launched the Per-sonalized Medicine Program in 2011 to ensure the clinical imple-mentation of PGx-based prescribing. The pilot implementationproject focused on implementation of clopidogrel-CYP2C19drug-gene pair and future plans include expansion to additionaldrug-gene pairs. The initiative developed a cost-effective PGxgenotyping array.56 A specialized hospital regulatory body isresponsible for regulating which clinically relevant PGx markersare migrated to the medical record and CDSS. As of March2013, CYP2C19 genotypes of 800 patients have been incorporat-ed in their medical records.57
344 VOLUME 101 NUMBER 3 | MARCH 2017 | www.cpt-journal.com
-
Tabl
e1
An
over
view
ofcu
rren
tcl
inic
alim
plem
enta
tion
stud
ies
and
prog
ram
sac
ross
the
Uni
ted
Sta
tes
and
Euro
pe
Impl
emen
tatio
nin
itiat
ive
Obj
ectiv
esC
linic
alsi
tes
(cou
ntry
)St
rate
gy
No.
PG
xge
nes
test
edP
latf
orm
Dru
g-ge
nepa
irsim
plem
ente
din
clin
ical
care
(clin
ical
guid
elin
es)
Pop
ulat
ion,
no.
Cle
vela
ndC
linic
’sPe
rson
aliz
edM
edic
atio
nPr
ogra
m3
0,4
7
-Impl
emen
ting
aC
DS
Sto
guid
eph
arm
acog
enet
-ic
ste
stor
derin
gan
dpr
ovid
ege
ne-b
ased
dos-
ing
reco
mm
enda
tions
atth
epo
int-o
f-car
e.In
par-
alle
l,a
PGx
cons
ulta
tion
serv
ice
isav
aila
ble.
-Cle
vela
ndC
linic
(US
A)-Im
plem
entin
gal
erts
that
reco
mm
end
orde
r-in
ga
PGx
test
atth
epo
int-o
f-car
e-Im
plem
entin
gdr
ug-g
ene
pairs
one
ata
time
N/A
N/A
HLA
-B*5
7:0
1/a
baca
vir
TPM
T/th
iopu
rines
(as
pert
heC
PIC
guid
elin
es)
Patie
nts
trea
ted
ina
ter-
tiary
care
adul
thos
pita
l,ch
ildre
n’s
hosp
ital,
regi
onal
hosp
ital,
oram
bula
tory
loca
tions
acro
ssO
hio
CLI
PMER
GE
PGx4
8,4
9-P
rovi
dein
sigh
tint
oth
em
echa
nism
s,to
ols,
and
proc
esse
sth
atw
illbe
stsu
ppor
tthe
use
ofPG
xin
clin
ical
care
-Con
trib
ute
toth
eem
erg-
ing
body
ofda
tane
eded
forf
orth
com
ing
larg
erst
udie
sth
atw
illas
sess
the
utili
tyof
PGx
inm
edi-
catio
nsa
fety
and
effic
acy
-Icah
nS
choo
lofM
edi-
cine
atM
ount
Sin
ai(U
SA)
Impl
emen
ting
pre-
empt
ive
geno
typi
ngan
dre
al-ti
me
CD
SS
depl
oyed
thro
ugh
the
EHR
into
rout
ine
care
usin
ga
bio-
bank
deriv
edco
hort
36
20
Seq
ueno
miP
LEX
ADM
EPG
x20
CYP
2C
19/c
lopi
dogr
elC
YP2
C9/w
arfa
rinVK
OR
C1
/war
farin
SLO
-C
O1
B1
/sim
vast
atin
CYP
2D
6/T
CAs
CYP
2C
19/T
CAs
CYP
2D
6/S
SR
Is(a
spe
rC
PIC
guid
elin
es)
Pilo
tstu
dy:p
rimar
yca
repa
tient
sw
hoco
nsen
ted
toB
ioM
Ebi
oban
k(N
51
,50
0).
Even
tual
aim
isto
recr
uita
llB
ioM
Epa
rtic
ipan
ts
eMER
GE-
PGx5
0–5
2-In
stal
lan
NG
Sse
quen
c-in
gpl
atfo
rmas
sess
ing
sequ
ence
varia
tion
inpa
tient
slik
ely
tobe
pre-
scrib
eda
drug
ofin
ter-
esti
na
1–3
-yea
rtim
efra
me
-Inte
grat
ecl
inic
ally
vali-
date
dge
noty
pes
into
the
EHR
and
CD
SS
and
toas
sess
the
impa
cton
clin
ical
outc
omes
and
proc
ess
ofim
plem
enta
tion
-Dev
elop
are
posi
tory
ofva
riant
sof
unkn
own
sig-
nific
ance
linke
dto
clin
i-ca
lphe
noty
peda
tato
expa
ndPG
xun
ders
tand
ing
-Bos
ton
Chi
ldre
n’s
Hos
pita
l-C
hild
ren’
sH
ospi
talo
fPh
ilade
lphi
a-C
inci
nnat
iChi
ldre
n’s
Hos
pita
l-G
eisi
nger
Hea
lthS
yste
m-G
roup
Hea
lth/U
nive
rsity
ofW
ashi
ngto
n-M
arsh
field
Clin
ic-M
ayo
Clin
ic(R
IGH
T)-Ic
ahn
Sch
oolo
fMed
i-ci
neat
Mou
ntS
inai
(CLI
PMER
GE)
-Nor
thw
este
rnU
nive
rsity
-Van
derb
iltU
nive
rsity
Med
ical
Cen
ter
(PR
EDIC
T)(a
llab
ove
inU
SA)
Mul
ticen
terp
roje
ctev
al-
uatin
gpr
e-em
ptiv
ese
quen
cing
and
pre-
empt
ive
geno
typi
ng
84
PGR
Nse
qVa
ries
acro
sscl
inic
alsi
tes
(as
perC
PIC
guid
elin
es)
Indi
vidu
als
likel
yto
bepr
escr
ibed
drug
sof
inte
rest
with
ina
1–3
-ye
artim
efra
me,
spec
ific
ther
apeu
ticfo
cus
amon
gal
lsite
s(N
59
,00
0)
IGN
ITE
(PG
xin
itiat
ives
)53
-To
deve
lop
met
hods
for,
and
eval
uate
the
feas
i-bi
lity
of,i
ncor
pora
ting
anin
divi
dual
patie
nt’s
geno
mic
info
rmat
ion
into
thei
rclin
ical
care
-Uni
vers
ityof
Flor
ida
(US
A)-V
ande
rbilt
Uni
vers
ity(U
SA)
-Indi
ana
Uni
vers
ity(U
SA)
Ane
twor
kof
heal
thca
resy
stem
sw
hoea
chim
plem
entP
Gx
inth
eir
site
N/A
N/A
N/A
N/A
Tabl
e1
Con
tinu
edon
next
page
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 3 | MARCH 2017 345
-
Tabl
e1
Con
tinu
ed
Impl
emen
tatio
nin
itiat
ive
Obj
ectiv
esC
linic
alsi
tes
(cou
ntry
)St
rate
gy
No.
PG
xge
nes
test
edP
latf
orm
Dru
g-ge
nepa
irsim
plem
ente
din
clin
ical
care
(clin
ical
guid
elin
es)
Pop
ulat
ion,
no.
ING
ENIO
US
54
,55
-To
asse
ssw
heth
erPG
xte
stin
gfo
rapa
nelo
fcl
inic
ally
rele
vant
mar
kers
impa
cts
annu
alhe
alth
care
cost
san
dad
vers
eev
enti
ncid
ence
-Indi
ana
Inst
itute
ofPe
r-so
naliz
edM
edic
ine
atIn
dian
aS
choo
lofM
edi-
cine
(US
A)
Ope
ratio
nali
mpl
emen
ta-
tion
ofpr
e-em
ptiv
ege
no-
typi
ngof
apa
nelo
fcl
inic
ally
rele
vant
mar
kers
inro
utin
eca
re,
ina
safe
ty-n
etho
spita
l
14
Ope
nar
ray
Clin
ical
lyre
leva
ntph
ar-
mac
ogen
esas
soci
ated
with
the
resp
onse
of2
8dr
ugs
(as
perC
PIC
guid
elin
es)
Adul
tpat
ient
sre
ceiv
ing
care
atth
eEs
kena
ziH
ealth
Sys
tem
(N5
6,0
00
)
Pers
onal
ized
Med
icin
ePr
ogra
m5
6,5
7
-Dev
elop
ing
apr
e-em
ptiv
e,ch
ip-b
ased
geno
typi
ngap
proa
chth
atis
cost
-effec
tive,
ini-
tially
fori
mpl
emen
tatio
nof
asi
ngle
drug
-gen
epa
irbu
teve
ntua
llyex
pand
ing
tom
any
othe
rs
-Uni
vers
ityof
Flor
ida
and
Sha
nds
Hos
pita
l(U
SA)
Impl
emen
ting
pre-
empt
ive
geno
typi
ngin
rout
ine
care
12
02
0Li
feTe
chno
logi
esQ
uant
Stu
dio
Ope
nAr
ray2
0
CYP
2C
19/c
lopi
dogr
el(a
spe
rCPI
Cgu
idel
ines
)Pa
tient
sre
ceiv
ing
anti-
plat
elet
ther
apy
and
unde
rgoi
ngpe
rcut
ane-
ous
coro
nary
inte
rven
-tio
n(N
58
00
)
PG4
KD
S5
8,5
9-U
ltim
atel
ym
igra
teal
lC
PIC
drug
-pai
rsin
toth
eEH
Ran
dC
DS
S
-St.
Jude
Chi
ldre
n’s
Res
earc
hH
ospi
tal(
US
A)R
esea
rch
prot
ocol
impl
emen
ting
pre-
empt
ive
geno
typi
ng
23
0Af
fym
etrix
DM
ETPl
usAr
ray
TPM
T,C
YP2
D6
,SL
OC
1B
1,a
ndC
YP2
C1
9co
uple
dto
12
high
-risk
drug
s(a
spe
rCPI
Cgu
idel
ines
)
St.
Jude
(ped
iatr
ic)
patie
nts
with
apr
imar
ym
edic
alre
cord
atS
t.Ju
deH
ospi
tal(
N5
1,5
59
)
PGR
N5
2-T
oas
sess
the
impl
e-m
enta
tion
ofro
utin
eev
iden
ce-b
ased
phar
ma-
coge
netic
test
ing
insi
xdi
vers
ehe
alth
care
syst
ems
-Uni
vers
ityof
Mar
ylan
d(U
SA)
-Uni
vers
ityof
Flor
ida
(US
A)-S
t.Ju
deC
hild
ren’
sR
esea
rch
Hos
pita
l(U
SA)
-Van
derb
iltU
nive
rsity
(US
A)-M
ayo
Clin
ic(U
SA)
-Ohi
oS
tate
Uni
vers
ity(U
SA)
Each
site
has
impl
e-m
ente
dph
arm
acog
eno-
mic
ste
stin
gof
one
orm
ore
drug
-gen
epa
irs,
both
thro
ugh
poin
t-of-
care
and
pre-
empt
ive
mod
els
N/A
N/A
Sev
eral
drug
-gen
epa
irsas
pert
heC
PIC
guid
elin
es
N/A
PRED
ICT2
1,6
0-T
oes
tabl
ish
afr
ame-
wor
kan
din
fras
truc
ture
forp
re-e
mpt
ive
inco
rpo-
ratio
nof
geno
mic
info
r-m
atio
nin
toth
eEH
R
-Van
derb
iltU
nive
rsity
Med
ical
Cen
ter(
US
A)O
pera
tiona
lim
plem
enta
-tio
nof
pre-
empt
ive
geno
-ty
ping
inro
utin
eca
re
34
Vera
Cod
eAD
ME
Cor
ePa
nel
CYP
2C
19/c
lopi
dogr
elC
YP2
C9/w
arfa
rinVK
OR
C1
/war
farin
(as
perC
PIC
guid
elin
es)
Patie
nts
rece
ivin
gan
ti-pl
atel
etth
erap
yfo
llow
-in
gpl
acem
ento
fca
rdio
vasc
ular
sten
t(N
51
0,0
00
)
Tabl
e1
Con
tinu
edon
next
page
346 VOLUME 101 NUMBER 3 | MARCH 2017 | www.cpt-journal.com
-
Tabl
e1
Con
tinu
ed
Impl
emen
tatio
nin
itiat
ive
Obj
ectiv
esC
linic
alsi
tes
(cou
ntry
)St
rate
gy
No.
PG
xge
nes
test
edP
latf
orm
Dru
g-ge
nepa
irsim
plem
ente
din
clin
ical
care
(clin
ical
guid
elin
es)
Pop
ulat
ion,
no.
RIG
HT6
1,6
2-D
evel
opbe
stpr
actic
esfo
rthe
impl
emen
tatio
nof
gene
ticse
quen
ceda
tain
tocl
inic
alsy
stem
s
May
oC
linic
(US
A)Im
plem
entin
gpr
e-em
ptiv
ese
quen
cing
and
geno
typi
ngin
rout
ine
care
84
PGR
Nse
qan
dLu
min
exC
YP2
D6
ASPE
kit
SLO
CO
1B
1/s
imva
stat
inC
YP2
C1
9/c
lopi
dogr
elIF
NL2
/int
erfe
ron
CYP
2D
6/t
ram
adol
CYP
2D
6/t
amox
ifen
CYP
2D
6/c
odei
neH
LA-B
*15
02/
carb
amaz
epin
eH
LA-B
*15
01/a
baca
vir
TPM
T/th
iopu
rines
(as
perC
PIC
guid
elin
es)
Patie
nts
likel
yto
rece
ive
stat
inth
erap
yw
ithin
3ye
ars,
recr
uite
dfr
omth
eM
ayo
Clin
icB
ioba
nk(N
51
,01
3)2
0
The
1,2
00
Patie
nts
Proj
ect6
3–6
5
-To
dete
rmin
eth
efe
asi-
bilit
yan
dut
ility
ofin
cor-
pora
ting
pre-
empt
ive
phar
mac
ogen
omic
ste
st-
ing
incl
inic
alca
re.
-Fut
ure
aim
sin
clud
eex
amin
ing
the
impa
ctof
prov
idin
gPG
xre
sults
onpr
escr
ibin
gde
cisi
ons
and
patie
ntou
tcom
es.
Uni
vers
ityof
Chi
cago
(US
A)O
bser
vatio
nals
tudy
impl
emen
ting
pre-
empt
ive
geno
typi
ng
N/A
Seq
ueno
mAD
ME
and
Seq
ueno
mcu
stom
pane
l
N/A
Adul
tsre
ceiv
ing
outp
a-tie
ntm
edic
alca
rean
dus
ing
1–6
pres
crip
tion
med
icat
ions
(N5
1,2
00
)
U-P
Gx
and
the
PREP
ARE
Stu
dy-Im
plem
enta
tion
ofpr
e-em
ptiv
ePG
xte
stin
g,of
apa
nelo
fclin
ical
lyre
le-
vant
mar
kers
-Ass
essi
ngth
eim
pact
onin
cide
nce
ofad
vers
eev
enti
ncid
ence
and
heal
thca
reco
sts
-Per
form
ing
expl
orat
ory
anal
yses
toex
pand
unde
rsta
ndin
gof
PGx
-Lei
den
Uni
vers
ityM
edi-
calC
ente
r(N
LD)
-Roy
alLi
verp
oolU
nive
rsi-
tyH
ospi
tal(
UK
)-U
nive
rsity
ofPa
tras
(GR
C)
-Uni
vers
ityof
Ljub
ljana
(SVN
)-M
edic
alU
nive
rsity
ofVi
enna
(AU
T)-N
atio
nalC
ance
rIns
ti-tu
teAv
iano
(ITA)
-Uni
vers
ityH
ospi
talG
ra-
nada
(ES
P)
Blo
ck-ra
ndom
ized
clin
i-ca
lstu
dyto
impl
emen
tpr
e-em
ptiv
ege
noty
ping
ofa
pane
lofc
linic
ally
rele
vant
mar
kers
.Add
i-tio
nalN
GS
sequ
enci
ngam
ong
thos
epr
esen
ting
extr
eme
phen
otyp
es
13
LGC
Gro
upS
NPl
ine
Clin
ical
lyre
leva
ntph
ar-
mac
ogen
esas
soci
ated
with
the
resp
onse
of4
3dr
ugs
(see
Tabl
e2
for
actio
nabl
edr
ug-g
ene
com
bina
tions
)(as
per
DPW
Ggu
idel
ines
)
Indi
vidu
als
who
rece
ive
afir
stpr
escr
iptio
nof
adr
ugof
inte
rest
.Firs
tlin
e,on
colo
gy,r
enal
,an
dliv
ertr
ansp
lant
,car
-di
olog
y,an
dps
ychi
atric
patie
nts
(N5
8,1
00
)
ADM
E,ab
sorp
tion,
dist
ribut
ion,
met
abol
ism
,elim
inat
ion;
AUT,
Aust
ria;C
DS
S,c
linic
alde
cisi
onsu
ppor
tsys
tem
;CPI
C,C
linic
alPh
arm
acog
enet
ics
Impl
emen
tatio
nC
onso
rtiu
m;D
PWG
,Dut
chPh
arm
acog
enom
ics
Wor
king
Gro
up;
EHR
,ele
ctro
nic
heal
thre
cord
;ES
P,S
pain
;GR
C,G
reec
e;H
LA,h
uman
leuc
ocyt
ean
tigen
;IG
NIT
E,Im
plem
entin
gG
enom
ics
inPr
actic
e;IN
GEN
IOU
S,I
Ndi
ana
GEN
omic
sIm
plem
enta
tion:
anO
ppor
tuni
tyfo
rthe
Und
erS
erve
d;IT
A,Ita
ly;N
/A,n
otap
plic
able
;NG
S,n
ext-g
ener
atio
nse
quen
cing
;NLD
,The
Net
herla
nds;
PGR
N,P
harm
acog
enom
ics
Res
earc
hN
etw
ork;
PGR
Nse
q,Ph
arm
acog
enom
ics
Res
earc
hN
etw
ork
sequ
enci
ng;P
Gx,
phar
mac
ogen
etic
;PR
E-D
ICT,
Phar
mac
ogen
omic
sR
esou
rce
forE
nhan
ced
Dec
isio
nsin
Car
ean
dTr
eatm
ent;
RIG
HTS
,Rig
htD
rug,
Rig
htD
ose,
Rig
htTi
me
stud
y;S
SR
I,se
roto
nin
reup
take
inhi
bito
r;S
VN,S
love
nia;
TCA,
tric
yclic
antid
epre
ssan
t;TP
MT,
thio
purin
eS
-met
hyltr
ansf
eras
e;U
K,U
nite
dK
ingd
om;U
-PG
x,U
biqu
itous
Phar
mac
ogen
omic
sC
onso
rtiu
m;U
SA,
Uni
ted
Sta
tes
ofAm
eric
a.
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 3 | MARCH 2017 347
-
PG4KDSThrough a research protocol, St. Jude Children’s Research Hospi-tal’s PG4KDS aims to selectively migrate PGx genotype tests intoroutine patient care so that results are available pre-emptively.Genotyping is performed using the DMET assay.58 The ultimateobjective is to migrate all CPIC drug-gene pairs into the EHR tofacilitate PGx-based prescribing and for it to ultimately becomeroutine care. A PGx oversight committee evaluates whether drug-gene pairs are qualified for migration into the EHR. Interruptivepretest alerts are fired when a drug linked to a drug-gene pair isprescribed, informing physicians that the patient does not yethave a documented genotype.29 Post-test alerts are fired when thegenotype is available in the patient’s EHR. Patients have theoption to consent to individualized notification every time a newgenetic test result is placed into their EHR. Additionally, educa-tional efforts are focused at both patients and clinicians. As ofAugust 2013, 1,559 patients had been enrolled and 4 genes and12 drugs have migrated to the EHR.59
Pharmacogenomics Research Network TranslationalPharmacogenetics ProgramIn 2011, the PGRN established the Translational Pharmacoge-netics Program to assess implementation within six diversehealthcare systems. The project’s aim is to assess the implementa-tion of routine evidence-based pharmacogenetic testing. Each sitewill implement PGx testing of one or more drug-gene pairs, asper the CPIC guidelines, either through a clinical trial or throughimplementing into clinical practice. Implementation strategiesinclude both through point-of-care and pre-emptive models. Pro-cess metrics for implementation are tracked among all sites toassess the effectiveness of implementation.52
Pharmacogenomics Resource for Enhanced Decisions in Careand Treatment ProjectAs part of the eMERGE-PGx project, Vanderbilt University hasinitiated the Pharmacogenomics Resource for Enhanced Deci-sions in Care and Treatment (PREDICT) project. The aim is todevelop the infrastructure and framework for incorporating PGxresults into the EHR and making these available to healthcareprofessionals at the time of prescribing. Initially, the implementa-tion focused on CYP2C19 genotyping for patients receiving anti-platelet therapy after having undergone cardiovascular stentinsertion. The enrollment focus is on groups of patients withanticipated cardiac catheterization with coronary artery stenting,but providers are not limited to enrolling patients within thistherapeutic area.21 As of November 2013, 10,000 patients hadbeen genotyped and several other drug-gene pairs have beenimplemented.60
Right drug, right dose, right timeAs part of the eMERGE-PGx project, the Mayo Clinic has initi-ated the Right Drug, Right Dose, Right Time (RIGHT) project.The aim of the project is to develop best practice for integratingboth PGx results and CDSS into the EHR to make PGx resultsavailable to prescribers pre-emptively at the point-of-care. As ofJuly 2013, 1,013 Mayo Clinic Biobank participants were included
in the study, four drug-gene pairs were approved for implementa-tion, and several others were under development for integrationwithin the CDSS.20 Initially, patients were eligible for enrollmentif they had a high risk of initiating statin therapy within 3 years,as this subset of patients would likely benefit from a PGx-drivenintervention. These participants were identified through a multi-variable prediction model.61 Pre-emptive PGx testing includedtargeted sequencing of 84 PGx genes and additional CYP2D6genotyping because of technical difficulties with sequencingCYP2D6. As an interim result, challenges have been identifiedthat require multidisciplinary and multi-institutional efforts tomake PGx-guided drug and dose selection routine care.62
The 1,200 Patients ProjectThe University of Chicago has initiated the 1,200 Patients Pro-ject and aims to determine the feasibility and utility of incorpo-rating pre-emptive PGx testing into clinical care. Thisobservational study involves the implementation of a novel geno-mic prescribing system to deliver a patient-specific interpretationof complex genomic data for a particular drug distilled into ashort summary.63 Outcomes of the study include whether physi-cians take PGx information into consideration and whether thisresults in altered prescribing patterns in patients at high risk foradverse drug reactions (ADRs) or nonresponse. Future aimsinclude an examination of the impact of providing PGx resultson prescribing decisions and patient outcomes.64 Followingrecruitment of 821 patients, initial results of the project demon-strate a high level of patient interest in PGx testing, and physicianadoption and utilization of PGx information through the geno-mic prescribing system.65
CURRENT PHARMACOGENOMICS IMPLEMENTATIONSTUDIES: TRENDS AND REMAINING RESEARCH GAPSFrom this overview, trends among initiatives and remainingknowledge gaps can be identified.
Trends across clinical implementation studiesSimilarities across clinical implementation studies include: inte-grating the PGx test results into the EHR and CDSS at thepoint-of-care to guide healthcare providers in using results inpatient care; implementation of the existing CPIC guidelines;implementing single drug-gene pairs one at a time and assessingtheir clinical utility; educating healthcare providers in PGx; andexpanding the field of PGx by making use of NGS techniques.Individual initiatives have additionally addressed the utility ofPGx in subpopulations, such as pediatrics59,67 and polypharma-cy,68,69 in which the impact of PGx may be greater.
Remaining knowledge gapsAlthough many implementation studies are addressing theremaining barriers, important knowledge and research gapsremain. One remaining gap is demonstrating quantifiable patientand economic benefit from a PGx testing strategy that focuses,not on a single drug-gene pair, but rather on a panel of pharma-cogenes across various therapeutic areas. This evidence couldenable evidence-based decision-making to shape policy. Further
348 VOLUME 101 NUMBER 3 | MARCH 2017 | www.cpt-journal.com
-
PGx investigations are also required to deepen our understandingof drug response phenotype-genotype associations. This deeperunderstanding of PGx is urgently needed to increase the predic-tive accuracy, benefits, and impact of PGx. An important addi-tional area for attention is the design of implementation modelsthat are transferable and feasible for institutes not as highly spe-cialized as the early adopting sites featured in Table 1.21,30,47–65
The U-PGx Consortium was established to address these criti-cal remaining research gaps in addition to observing the afore-mentioned state-of-the-art trends. The U-PGx Consortiumstrives to provide evidence regarding the clinical utility of PGxtesting using a panel of pharmacogenes, provide evidence of cost-effectiveness, and to expand the field of PGx by both NGS andsystems pharmacology approaches. U-PGx is one of the fewimplementation studies assessing the combined clinical utility ofmultiple drug-gene pairs and is, therefore, strategy-specific asopposed to drug-gene pair-specific. U-PGx is also the first toimplement PGx across countries, and, therefore, across many eth-nicities and healthcare systems. U-PGx is also not limited toimplementing PGx in highly specialized institutions, and there-fore, will obtain different process metrics for implementationthan early adopting institutions, in which providers may havemore PGx knowledge. U-PGx is also the first study implementingthe DPWG guidelines, as opposed to the CPIC guidelines. Simi-lar to many implementation studies, U-PGx will integrate PGxresults into the workflow of healthcare providers, aims to educateboth physicians and pharmacists in PGx, and measure processmetrics for implementation.
UBIQUITOUS PHARMACOGENOMICS CONSORTIUMOvercoming implementation barriersEnabling tools. As of October 2016, a variety of enabling toolshave been developed to facilitate implementation of PGx testingin a wide range of healthcare systems across the European Union.A detailed analysis of existing data management systems (bothelectronic and paper-based) at clinical sites has been conductedto guide the development of CDSS implementation strategies inU-PGx. To accommodate the widely varying capabilities andneeds of data management systems at different implementationsites, a spectrum of complementary CDSS solutions were devel-oped. Specifically, to make PGx data and CDSS available inhealth care systems in which an EHR is unavailable, the “Safety-Code card” has been adopted.70 This card is part of a mobile-based CDSS called the Medication Safety Code system that isindependent of existing information technology infrastructures,and enables quick retrieval of patient-relevant PGx drug dosingguidelines (Figure 3). The Medication Safety Code system doesnot require central patient data storage. Instead, the “Safety-Codecard” contains a quick response code that stores the patient’sencoded PGx results. It can be decoded and interpreted by com-mon smartphones and other devices. After scanning the quickresponse code, the medical professional is led to a website thatprovides drug-dosing recommendations customized to the PGxprofile of the patient. In the context of PREPARE, the Medica-tion Safety Code system is aimed to serve as an auxiliary tool tomaximize the accessibility and sharing of PGx results within and
between different healthcare settings and healthcare professionals.Patients will be asked to show their “Safety-Code card” to physi-cians and pharmacists who prescribe or dispense drugs to themduring the follow-up period of the study. Thus, these physiciansand pharmacists can use the patient’s PGx results to guide drugand dose selection. Concomitantly, patients will be asked toreport prescriptions of additional newly started drugs to researchnurses during the follow-up period.Knowledge base curation and the automated translation of
genetic data to associated phenotypes and recommendations willbe handled by the Genetic Information Management Suite creat-ed by the U-PGx partner bio.logis Genetic Information Manage-ment.71 The Genetic Information Management Suite DiagnosticReport Module holds the CE mark according to EEC 93/42, EC2007/47. The CE mark for a medical device not only certifies theproduct’s quality according to valid European guidelines, but alsoconfirms its fitness to be used for the intended medical purpose.The authorities responsible for monitoring the manufacturer’scompliance with the relevant European regulations are the Ger-man Institute of Medical Documentation and Information aswell as the Federal Institute for Drugs and Medical Devices. Inaddition, the Diagnostic Report Module has been certified as an“internet medicine quality product” by the Federal Associationfor Internet Medicine.
The Dutch Pharmacogenomics Working Group guidelines. In 2005,the Royal Dutch Pharmacists Association established the DPWGwith the objective to develop pharmacogenetic-based therapeuticrecommendations based on a systematic review of the literature.The DPWG consists of 14 members, including clinical pharma-cists, community pharmacists, general practitioners, physicians,clinical chemists, epidemiologists, and a toxicologist. Currently,the database consists of 84 drug-gene pairs comprising 13 genes.DPWG guidelines are integrated in the “G-Standaard” (theDutch national drug database) and are incorporated into allelectronic systems for drug prescribing and dispensing in TheNetherlands. As part of U-PGx, the DPWG guidelines31,32 havebeen translated into all local languages (from Dutch to English,German, Greek, Slovenian, Spanish, and Italian) by certifiedprofessionals.
Genotyping platform and variant selection. The LGC GroupSNPline platform will be deployed at all implementation sites,ensuring homogenous genotyping across the project. TheSNPline platform is a flexible and scalable solution for polymer-ase chain reaction-based genotyping. It comprises a workflowthat enables the user to generate up to more than 1,000,000 datapoints per day. Additionally, it retains the flexibility to run indi-vidual repeats without consuming arrays and producing far moredata than needed. The variants included in the panel were select-ed systematically by prespecified criteria. The criteria for variantselection are listed in Supplementary Table S1 online. Theselection yielded 50 variants in 13 pharmacogenes. Variantsincluded in the panel and their associated phenotypes are listedin Supplementary Table S2 online.
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 3 | MARCH 2017 349
-
Pharmacogenomics education. Provider and patient educationand support are crucial for successful implementation of PGx. E-Learning programs will be prepared with the aim of developingan e-learning based knowledge platform for the participatingcountries and partners. This e-learning platform will be used todistribute the PGx knowledge required by physicians and phar-macists to make use of PGx in patient care. Using electronic edu-cation methods, lectures will cover the main themes that areregarded necessary for the use and implementation of PGx andwill be offered to schools of medicine, schools of pharmacy, andpost-academics. These will cover the basics of PGx, drug metabo-lism, drug dosing, targeted therapies, regulations and guidelinesfor PGx diagnostics in drug development and pharmacovigilance,companion diagnostics, obligatory genetic tests, good genomicpractice, and PGx information in drug labels. The level of knowl-edge and opinion on PGx among physicians and pharmacists at
the start and at the end of the project will be investigatedthrough surveys. The aim is to assess the level of knowledge aboutPGx among healthcare professionals to identify knowledge gapsthat may hinder the implementation of PGx testing in routinecare.
The PREPARE studyOverall study design. PREPARE is an international prospective,multicenter, open, block-randomized study. Figure 4 illustratesthe PREPARE study design. The PREPARE study (Clinicaltrials.gov Number – registration pending) will investigate the impactof pre-emptive genotyping of a panel of clinically relevant PGx-markers on patient outcomes. It is unique in its multicenter, mul-tigene, multidrug, multi-ethnic, and multihealthcare systemapproach. It is hypothesized that implementing PGx-guided drugand dose selection will decrease clinically relevant ADRs by 30%
Figure 3 The front (top) and back (bottom) of the “Safety-Code card.” This is a plastic card, akin to a credit card, carrying an individual’s pharmacogeno-mic information and a quick response (QR) code, which is connected to the individual’s personalized dosing recommendations, as per the Dutch Pharma-cogenomics Working Group. TPMT, thiopurine S-methyltransferase; U-PGx, Ubiquitous Pharmacogenomics (U-PGx) Consortium.
350 VOLUME 101 NUMBER 3 | MARCH 2017 | www.cpt-journal.com
http://Clinicaltrials.govhttp://Clinicaltrials.gov
-
(from 4–2.8%). Pre-emptive PGx testing will be implemented inclinical sites across seven European countries (United Kingdom,The Netherlands, Austria, Greece, Slovenia, Italy, and Spain).The PREPARE protocol has been submitted for ethical approval,locally, in all seven countries. The study will be performed inaccordance with the Helsinki Declaration of 1975 (as revised in1983). The 36-month study is split into two 18-month blocks.The participating countries are randomized to start with eitherimplementing PGx-guided prescribing or with standard of carefor the first block. After this 18-month block, the countriesswitch to implementing the opposite strategy and will recruitnew patients (i.e., patients recruited into one of the arms cannotbe re-recruited into the other arm). Both patients and researchteams cannot be blinded; the PGx results will be used to guidedrug and dose selection, and patients will receive their PGxresults on a “Safety-Code card.” In total, 8,100 patients will berecruited; 4,050 patients in the intervention arm and 4,050patients in the control arm. Each implementation site will con-centrate on, but is not limited to, recruiting patients within a spe-cific therapeutic area. Therapeutic areas include primary care,general medicine, cardiology, oncology, psychiatry, neurology,and transplantation. The PREPARE study schema is illustratedin Figure 5.
Patient recruitment. Adult patients who receive a first prescrip-tion for a drug listed in Table 2 (drugs for which a DPWG dos-ing recommendation is available), within routine care, will beidentified and are eligible for inclusion. Inclusion and exclusioncriteria are listed in Supplementary Table S3 online. The first
drug that is included is referred to as the “index drug.” To ensurethat there is a balanced patient and drug population among inter-vention and control arms, inclusion of any given index drug islimited to 10% in both the intervention (n 5 405) and controlarms (n 5 405).
Drug selection. DPWG guidelines to guide dose and drug selectionare available for more drugs than are included in the PREPAREstudy. Table 2 includes all drugs for which an actionable drug-geneinteraction is present, according to the DPWG recommendationswith the exception of abacavir, omeprazole, esomeprazole, lansopra-zole, pantoprazole, and rabeprazole. Abacavir is excluded becausePGx-guided prescribing is mandatory in routine care. Proton pumpinhibitors are excluded because the DPWG recommendations areonly associated with differences in efficacy, rather than ADR fre-quency, among aberrant genotypes (in which ultra-rapid metaboliz-ers are recommended a higher dose to ensure sufficient blood levelsfor an efficacious pharmacotherapy). Estrogen-containing drugs willnot serve as an index drug, but are incorporated into the study ifnewly started in a patient already recruited onto PREPARE duringstudy follow-up (see below “subsequent drugs”).
The pharmacogenomics intervention. A DNA sample is collectedat recruitment for genotyping of a panel of 50 variants in 13pharmacogenes. The PGx results of patients in the study armonly will be used to guide drug and dose selection, as per theDPWG guidelines. These results will be provided to the prescrib-ing physician or dispensing pharmacist with a maximum turnovertime of 3 working days.
Figure 4 Timeline of the PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions (PREPARE) study: in the first year all toolsenabling pre-emptive pharmacogenomics (PGx) testing (information technology, genotyping technology, education, translation, and sharing of guidelines)will be prepared and finalized. In years 2–4, the impact of pre-emptive PGx testing will be evaluated in the PREPARE study. Sites (countries where thestudy is performed) are block-randomized to either implement PGx-guided prescribing or standard of care for an 18-month block. After this 18-monthblock, the opposite strategy will be implemented, with a new set of recruited patients. A total of 4,050 new patients will be recruited in each block. Eachsite will function as its own control. In parallel, data will be collected for innovative projects, which aim to expand the understanding of pharmacogenomicsthrough next-generation sequencing and systems pharmacology approaches.
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 3 | MARCH 2017 351
-
Follow-upFollow-up by the research team will assess incident adverse drugevents, (index) drug modifications, drug adherence, quality of life,costs, comedication, and attitudes toward PGx. Assessment ofADRs will be performed by the research team and will involve
causality, severity, and genotype correlation assessments. IncidentADRs collected by the research team will contribute to the pri-mary composite endpoint (see “primary composite endpoint”).The research team will contact patients at 4 weeks, 12 weeks, andat the end of the study arm by telephone (outpatients) or in
Figure 5 Study logistics in the PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions (PREPARE) study. Adult patients receivinga first prescription for one of the 42 included drugs will be identified and are eligible for inclusion. At recruitment, a DNA sample is collected for genotypingof a panel of 50 variants in 13 pharmacogenes. The pharmacogenomics (PGx) results of patients in the intervention arm only will be used to guide drugand dose selection as per the Dutch Pharmacogenomics Working Group (DPWG) guidelines. Patients in the intervention arm will receive a “Safety-Codecard” containing their personal PGx results, which can be used by other physicians or pharmacists to guide subsequent prescriptions. Patients in thestandard of care arm will receive a mock “Safety-Code card,” not containing any PGx results but listing the Ubiquitous Pharmacogenomics Consortium eli-gible drugs. There are two consecutive 18-month blocks for recruitment of participants. In one block, participants will receive standard of care; in the oth-er block, other participants will receive the PGx intervention. The order of these blocks is randomized at each study site. Following recruitment, allpatients will be followed-up for 3 months, both by the research nurse (at baseline, 4 weeks, and 12 weeks after initiating the index drug) and by an onlinepatient-reported outcomes survey (at 2 weeks and 8 weeks). In addition, a final cross-sectional survey will be performed by the research nurse at the endof the study arm. Follow-up will assess for incident adverse drug events, drug modifications, drug adherence, quality of life, healthcare costs, comedica-tion, and attitudes toward PGx. Assessment of adverse drug reactions will be performed by the research team and involves a causality, severity, and geno-type correlation assessment. Patients are requested to report if they newly start any of the 43 drugs (including estrogen-containing drugs) of interestduring follow-up in addition to the index drug. This will trigger an identical 3-month follow-up.
352 VOLUME 101 NUMBER 3 | MARCH 2017 | www.cpt-journal.com
-
Table 2 Actionable drug-gene pairs implemented in routine care in the PREPARE study, as per the Dutch Pharmacogenomics Work-ing Group guidelines
Drug class Drug (n 5 43)Clinically relevantgenetic interaction Actionable phenotypes/genotypes
Antiarrhythmic Flecainide CYP2D6 PM, IM, UM
Propafenon CYP2D6 PM, IM, UM
Analgesic Codeine CYP2D6 PM, IM, UM
Oxycodone CYP2D6 PM, IM, UM
Tramadol CYP2D6 PM, IM, UM
Anticancer Capecitabine DPD Gene activity score 0, 0.5, 1.0, 1.5
Fluorouracil DPD Gene activity score 0, 0.5, 1.0, 1.5
Irinotecan UGT1A1 PM, *28/*28
Tamoxifen CYP2D6 PM, IM
Tegafur DPD Gene activity score 0, 0.5, 1.0, 1.5
Anticoagulation Acenocoumarol VKORC1 VKORC1TT
Clopidogrel CYP2C19 PM, IM
Phenprocoumon VKORC1 VKORC1TT
Warfarin CYP2C9VKORC1
*1/*3, *2/*2, *2/*3, *3/*3, IM, PM, TT
Antidepressant Citalopram CYP2C19 PM, IM
Escitalopram CYP2C19 PM, IM
Paroxetine CYP2D6 UM
Sertraline CYP2C19 PM, IM
Venlafaxine CYP2D6 PM, IM, UM
Antidepressant (TCA) Amitriptyline CYP2D6 PM, IM, UM
Clomipramine CYP2D6 PM, IM, UM
Doxepin CYP2D6 PM, IM, UM
Imipramine CYP2D6CYP2C19
PM, IM, UMPM
Nortriptyline CYP2D6 PM, IM, UM
Antiepileptic Carbamazepine HLA B*5701 –
Phenytoin CYP2C9 IM, PM, *1/*2, *1/*3, *2/*2, *2/*3, *3/*3
Antihypertensive Metoprolol CYP2D6 PM, IM, UM
Anti-infective Efavirenz CYP2B6 PM, IM
Flucloxacillin HLA B*5701 –
Voriconazole CYP2C19 PM, IM
Antipsychotic Aripiprazole CYP2D6 PM
Clozapine CYP1A2 *1C heterozygote, *1C/*1C
Haloperidol CYP2D6 PM, UM
Pimozide CYP2D6 PM, IM
Zuclopenthixol CYP2D6 PM, IM, UM
Cholesterol-lowering Atorvastatin SLCO1B1 521TC, 521CC
Simvastatin SLCO1B1 521TC, 521CC
Table 2 Continued on next page
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 3 | MARCH 2017 353
-
person (inpatients). Various open questions will be posed to iden-tify adverse events experienced by the patient, followed by a seriesof closed questions to identify specific adverse events associatedwith the drug of interest.In parallel, patient-reported outcomes will be monitored
through an established web-based platform developed by theNetherlands Pharmacovigilance Center Lareb, and will only beused as a secondary outcome. This web-based intensive monitor-ing system has been validated in several clinical trials as a feasibleand accurate method for collecting adverse drug event data.72
This aspect of the study is important as patient-reported adverseevents may differ from those collected by the research team.73
Reporting patients will provide assessments of severity and causal-ity of their own adverse event. Patient-reported severity willbe measured by using a scale based on the Patient-ReportedOutcome-Common Toxicity Criteria.74
Subsequent prescriptions of drugs of interest. Patients arerequested to notify the research team every time they receive aprescription for one of the 43 drugs of interest (as listed inTable 2) during follow-up. These drugs are referred to as“subsequent drugs.” This will trigger an identical 3-month fol-low-up as for the index drug (as illustrated in Figure 5). Patientsare requested to provide their (mock) “Safety-Code card” to phy-sicians who manage them or dispensing pharmacists. Healthcareproviders will have the ability to make use of the PGx results toguide drug and dose selection at the point of consultation; in thecontrast to the index drug, in which a 3 workday lag-time isunavoidable. There is recognition for the fact that the researchteam is fully reliant on patient-reported subsequent prescriptions,in order to trigger follow-up for this subsequent prescription.This could introduce selection bias. Therefore, incident ADRsresulting from subsequent prescriptions will only be used as a sec-ondary outcome.
Primary composite outcome. All adverse events are monitoredduring follow-up by the research team and are classified accordingto causality, severity, and drug-genotype association. Causalitywill be classified using the Liverpool Causality AssessmentTool.75 Severity will be classified using the National Cancer Insti-tute Common Toxicity Criteria for Adverse Events scale. The
drug-genotype association will be assessed using the DPWGguidelines.31,32 To ensure homogenous assessment across all sites,the Netherlands Pharmacovigilance Center Lareb will blindlyreassess a random selection of adverse drug events. Adverse drugevents contributing to the composite primary endpoint are illus-trated in Figure 6. All ADRs that contribute to the primary end-point, contribute equally, regardless of their severity.
Primary analysis. A gatekeeping analysis will be performed for theprimary analysis only among patients who had an actionabledrug-genotype combination for the index drug. This first analysiswill compare the fraction of patients who experienced at leastone clinically relevant ADR within the 12-week follow-up, attrib-utable to the index drug, between the standard of care and theintervention arm. If this is statistically significant, a second analy-sis will be performed, including all patients in the study. Thissecond analysis will compare the fraction of patients who experi-enced at least one clinically relevant ADR within the 12-weekfollow-up attributable to the index drug, between the standard ofcare and the intervention arm. All sites will act as their own con-trols. The first analysis will quantify the absolute impact of PGx-based prescribing on the frequency of clinically relevant ADRs;the second will quantify the impact of PGx intervention when itis implemented population-wide.
Secondary outcomes. Drug efficacy is not an outcome measure inthe PREPARE study. It is not anticipated that PGx-guided pre-scribing will have a negative impact on drug efficacy. To provideevidence for this statement, two proxy measures of efficacy willbe collected. First, the frequency of drug discontinuation becauseof lack of efficacy will be compared in the standard of care armto the intervention arm. Second, routine index drug levels ofpatients who received a dose alteration because of an actionabledrug-gene combination will be compared to the routine indexdrug levels of patients who did not receive a dose alteration. It ishypothesized that the drug exposures are similar in both arms,and, therefore, that efficacy must be similar. Data on costs associ-ated with ADRs will be collected to perform a country-specificcost-effectiveness analysis. Adherence to PGx guidelines will alsobe collected following every index drug and subsequent drug pre-scription within the PREPARE study. This will yield data on
Table 2 Continued
Drug class Drug (n 5 43)Clinically relevantgenetic interaction Actionable phenotypes/genotypes
Immunosuppressive Azathioprine TPMT PM, IM
Mercaptopurine TPMT PM, IM
Tacrolimus CYP3A5 Homozygote or heterozygote expressers
Thioguanine TPMT PM, IM
Other Atomoxetine CYP2D6 PM, UM
Estrogen containing drugsa FVL Homozygote expresser, Heterozygote expresser
CYP, cytochrome P450; DPD, dihydropyrimidinedehydrogenase; FVL, factor five Leiden HLA, human leucocyte antigen; SLCO, solute carrier organic anion transporter;TPMT, thiopurine S-methyltransferase; UGT, UDP-glucuronosyltransferase; VKORC, vitamin K oxide reductase complex.aOnly included for follow-up as a subsequent prescription, not for a drug of inclusion.
354 VOLUME 101 NUMBER 3 | MARCH 2017 | www.cpt-journal.com
-
DPWG guideline adherence by both the healthcare professionalswho recruit to the PREPARE study and the healthcare professio-nals outside the scope of the PREPARE study but who managean episode of routine care for a participant during the studyfollow-up period. The research team will contact healthcare pro-fessionals after they have received their patient’s PGx results toask whether they complied with the DPWG recommendation.When healthcare professionals do not comply with the recom-mendation, they are asked to report reasons for not doing so.Patient knowledge of and attitudes toward PGx will also be col-lected at baseline and at the end of the study.
A step into the futurePGx is still an evolving discipline and will undoubtedly be furtherdeveloped over the years to increase the applicability and subse-quent impact of PGx on patient outcomes. Our incompleteunderstanding of the genetic impact on drug responses limits thebenefits of PGx in clinical care; possibly up to 50% of ADRs maybe predicted by common genetic determinants. Rare variants mayalso be associated with drug responses or ADRs; using NGS76–79
and systems pharmacology approaches, we may be able to increaseour understanding of the role of PGx and thereby potentiallyincrease its benefits and impact. The U-PGx Consortium willachieve this by using two approaches: (1) NGS techniques toidentify rare variants that are associated with drug response inthe extreme phenotype substudy; and (2) through a systems phar-macology approach, nongenetic determinants of drug response(such as gender, age, and drug-drug interaction) will be integrated
to create novel, powerful, and practice-oriented models of person-alized medicine in pharmacokinetic substudies. Inclusion andexclusion criteria for the substudies are listed in SupplementaryTable S4 online.
Extreme phenotype substudy. Patients included in the PREPAREstudy who: (1) experience a serious ADR, which is not expectedon the basis of the pre-emptive PGx testing results in the PGxintervention arm; (2) experience a serious ADR (already knownto be associated with the drug in the DPWG guidelines) eventhough the patient has received an altered drug or dose selectionas a result of an actionable genotype; or (3) experience a seriousADR in the PGx control arm. These “extreme phenotype”patients will be flagged and contacted by the research nurse toobtain a blood sample for drug level monitoring at the time ofthe ADR for NGS sequencing and detection of plasma levels ofthe drug of interest, including relevant metabolites. NGSsequencing will be performed to search for novel variants associ-ated with the extreme phenotype. To identify a possible geneticorigin of the extreme phenotype, all patients included in thestudy will be asked to provide informed consent for NGS. Thesedata will only be used anonymously for exploratory analysis andnot be implemented in clinical care or returned to the patient,thereby no potential secondary genetic findings will be returnedto the patients. Plasma samples of drugs of interest will bedetected by previously established methods (e.g., high perfor-mance liquid chromatography, liquid chromatography tandem
Figure 6 The primary endpoint is the frequency of clinically relevant adverse drug reactions within 3 months of initiating the index drug. All incidentadverse drug events (ADEs) will be assessed regarding causality (using the Liverpool Causality Assessment Tool), severity (using the National CancerInstitute Common Toxicity Criteria for Adverse Events [NCI-CTCAE] scale), and association to genotype (using the Dutch Pharmacogenomics WorkingGroup [DPWG] guidelines). Only ADEs defined as definitely, probably, or possibly adverse drug reactions (ADRs), according to the Liverpool causalityassessment tool, classified as severe (defined as NCI-CTCAE grades 2, 3, 4, or 5), and associated with a drug-genotype pair contribute to the primaryendpoint.
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 3 | MARCH 2017 355
-
mass spectrometry) to perform additional phenotype (plasmalevel)-genotype correlation analysis.
Pharmacokinetic substudy. Patients included in the study after afirst prescription of voriconazole, metoprolol, simvastatin, atorva-statin, fluorouracil, or capecitabine will be asked to provide addi-tional blood samples (see Supplementary Table S5 online) toquantify levels of the parent drug and respective metabolites.Through a systems pharmacology approach, nongenetic determi-nants of drug response (such as gender, age, disease-related fac-tors, and drug-drug interaction) will be integrated to create novel,powerful, and practice-oriented models of personalized medicine.This work will strive toward assessing the relative contribution ofPGx to variability in drug response by utilizing pharmacometricmodels that integrate PGx with other sources of variability. Themodels will describe the events from dose to drug response, thusincluding effects of PGx on pharmacokinetics and pharmacody-namics. Physiologically based pharmacokinetic models and/orpopulation pharmacokinetic models will be utilized. Clinical end-point data as well as clinically relevant drug-drug interactions willbe extracted from PREPARE to be used for adjustment and qual-ification of model-based analyses.
CONCLUSIONSIn conclusion, the U-PGx Consortium will implement pre-emptive PGx testing involving a panel of pharmacogenes intoroutine care to guide drug and dose selection for 43 drugs,through a multicenter, block-randomized controlled study. PRE-PARE aims to assess the impact of implementation on ADR inci-dence and healthcare costs. In parallel, innovative approaches,such as pharmacometric modeling, NGS, and systems pharmacol-ogy, will be used to expand our understanding of PGx and there-by increase its potential benefits and impact.We hypothesize successful PGx implementation could drasti-
cally decrease the incidence of ADRs and could increase the bene-fit: risk profile of pharmacotherapy. Currently, unacceptablelevels of ADRs, poor adherence, and ineffectiveness are associatedwith pharmacotherapies for many conditions. Each year, adversedrug events are responsible for 5% of hospitalizations, but, cru-cially, PGx implementation has the potential to alleviate this.The impact of PGx testing will be maximized when implementedpopulation-wide. Because actionable PGx variants are ubiquitousand the results of PGx testing are life-long, we foresee a future inwhich everyone undergoes PGx testing. Physicians and pharma-cists can use these results pre-emptively to optimize drug anddose selection throughout a patient’s lifetime. This could ulti-mately decrease (but not abolish) the incidence of ADRs andtheir associated healthcare service and societal burdens.
Additional Supporting Information may be found in the online version ofthis article.
ACKNOWLEDGMENTSThe research leading to these results has received funding from theEuropean Community’s Horizon 2020 Programme under grantagreement No. 668353 (U-PGx). M.S. and E.S. are supported in part bythe Robert Bosch Stiftung, Stuttgart, Germany.
CONFLICT OF INTERESTG.P.P. is Full Member and National Representative of the Committee forHuman Medicinal Products (CHMP)-Pharmacogenomics Working Party ofthe European Medicines Agency (London, UK). M.S. and E.S. are contrib-utors to a patent application related to a diagnostic test for detection ofTPMT deficiency.
AUTHOR CONTRIBUTIONSC.H.v.d.W., A.C.-T., E.C., K.-C.C., C.L.D.-F., V.H.D., V.D., S.J., M.O.K.,M.K., C.M., G.P.P., M.P., M.S., E.S., M.S., D.S., J.S., R.M.T., M.H.v.R.,S.J.S., and H.-J.G. wrote the manuscript and designed the research. M.I.-S.and G.S.-P. reviewed the manuscript and designed the research
VC 2016 American Society for Clinical Pharmacology and Therapeutics
1. Hamburg, M.A. & Collins, F.S. The path to personalized medicine. N.Engl. J. Med. 363, 301–304 (2010).
2. Green, E.D., Guyer, M.S. & National Human Genome ResearchInstitute. Charting a course for genomic medicine from base pairs tobedside. Nature 470, 204–213 (2011).
3. Relling, M.V. & Evans, W.E. Pharmacogenomics in the clinic. Nature526, 343–350 (2015).
4. Weinshilboum, R. & Wang, L. Pharmacogenomics: bench to bedside.Nat. Rev. Drug Discov. 3, 739–748 (2004).
5. Wu, A.C. & Fuhlbrigge, A.L. Economic evaluation of pharmacogenetictests. Clin. Pharmacol. Ther. 84, 272–274 (2008).
6. Pirmohamed, M. Personalized pharmacogenomics: predicting efficacyand adverse drug reactions. Annu. Rev. Genomics Hum. Genet. 15,349–370 (2014).
7. Guchelaar, H.J., Gelderblom, H., van der Straaten, T., Schellens, J.H.& Swen, J.J. Pharmacogenetics in the cancer clinic: from candidategene studies to next-generation sequencing. Clin. Pharmacol. Ther.95, 383–385 (2014).
8. Pirmohamed, M. et al. A randomized trial of genotype-guided dosingof warfarin. N. Engl. J. Med. 369, 2294–2303 (2013).
9. Wu, A.H. Pharmacogenomic testing and response to warfarin. Lancet385, 2231–2232 (2015).
10. Verhoef, T.I. et al. A randomized trial of genotype-guided dosing ofacenocoumarol and phenprocoumon. N. Engl. J. Med. 369, 2304–2312 (2013).
11. Coenen, M.J. et al. Identification of patients with variants in TPMTand dose reduction reduces hematologic events during thiopurinetreatment of inflammatory bowel disease. Gastroenterology 149,907–917 (2015).
12. Mallal, S. et al. HLA-B*5701 screening for hypersensitivity toabacavir. N. Engl. J. Med. 358, 568–579 (2008).
13. Chen, P. et al. Carbamazepine-induced toxic effects and HLA-B*1502screening in Taiwan. N. Engl. J. Med. 364, 1126–1133 (2011).
14. Ko, T.M. et al. Use of HLA-B*58:01 genotyping to prevent allopurinolinduced severe cutaneous adverse reactions in Taiwan: nationalprospective cohort study. BMJ 351, h4848 (2015).
15. Altman, R.B. Pharmacogenomics: “noninferiority” is sufficient forinitial implementation. Clin. Pharmacol. Ther. 89, 348–350 (2011).
16. van der Wouden, C.H., Swen, J.J., Samwald, M., Mitropoulou, C.,Schwab, M. & Guchelaar, H.J. A brighter future for theimplementation of pharmacogenomic testing. Eur. J. Hum. Genet. 24,1658–1660 (2016).
17. Pirmohamed, M. & Hughes, D.A. Pharmacogenetic tests: the need fora level playing field. Nat. Rev. Drug Discov. 12, 3–4 (2013).
18. Khoury, M.J. Dealing with the evidence dilemma in genomics andpersonalized medicine. Clin. Pharmacol. Ther. 87, 635–638 (2010).
19. Relling, M.V., Altman, R.B., Goetz, M.P. & Evans, W.E. Clinicalimplementation of pharmacogenomics: overcoming geneticexceptionalism. Lancet Oncol. 11, 507–509 (2010).
20. Dunnenberger, H.M. et al. Preemptive clinical pharmacogeneticsimplementation: current programs in five US medical centers. Annu.Rev. Pharmacol. Toxicol. 55, 89–106 (2015).
21. Van Driest, S.L. et al. Clinically actionable genotypes among 10,000patients with preemptive pharmacogenomic testing. Clin. Pharmacol.Ther. 95, 423–431 (2014).
356 VOLUME 101 NUMBER 3 | MARCH 2017 | www.cpt-journal.com
-
22. Swen, J.J. et al. Translating pharmacogenomics: challenges on theroad to the clinic. PLoS Med. 4, e209 (2007).
23. Abbasi, J. Getting pharmacogenomics into the clinic. JAMA 316,1533–1535 (2016).
24. Haga, S.B. & Burke, W. Pharmacogenetic testing: not as simple as itseems. Genet. Med. 10, 391–395 (2008).
25. Deverka, P.A., Doksum, T. & Carlson, R.J. Integrating molecularmedicine into the US health-care system: opportunities, barriers, andpolicy challenges. Clin. Pharmacol. Ther. 82, 427–434 (2007).
26. Altman, R.B., Kroemer, H.K., McCarty, C.A., Ratain, M.J. & Roden, D.Pharmacogenomics: will the promise be fulfilled? Nat. Rev. Genet.12, 69–73 (2011).
27. Perry, C.G. et al. Educational innovations in clinicalpharmacogenomics. Clin. Pharmacol. Ther. 99, 582–584 (2016).
28. Frick, A. et al. Transitioning pharmacogenomics into the clinicalsetting: training future pharmacists. Front. Pharmacol. 7, 241 (2016).
29. Bell, G.C. et al. Development and use of active clinical decisionsupport for preemptive pharmacogenomics. J. Am. Med. Inform.Assoc. 21, e93–e99 (2014).
30. Hicks, J.K. et al. Implementation of clinical pharmacogenomics withina large health system: from electronic health record decision supportto consultation services. Pharmacotherapy 36, 940–948 (2016).
31. Swen, J.J. et al. Pharmacogenetics: from bench to byte--an update ofguidelines. Clin. Pharmacol. Ther. 89, 662–673 (2011).
32. Swen, J.J. et al. Pharmacogenetics: from bench to byte. Clin.Pharmacol. Ther. 83, 781–787 (2008).
33. Relling, M.V. & Klein, T.E. CPIC: Clinical PharmacogeneticsImplementation Consortium of the Pharmacogenomics ResearchNetwork. Clin. Pharmacol. Ther. 89, 464–467 (2011).
34. Birdwell, K.A. et al. Clinical Pharmacogenetics ImplementationConsortium (CPIC) guidelines for CYP3A5 genotype and tacrolimusdosing. Clin. Pharmacol. Ther. 98, 19–24 (2015).
35. Caudle, K.E. et al. Clinical pharmacogenetics implementationconsortium guidelines for CYP2C9 and HLA-B genotypes andphenytoin dosing. Clin. Pharmacol. Ther. 96, 542–548 (2014).
36. Clancy, J.P. et al. Clinical Pharmacogenetics ImplementationConsortium (CPIC) guidelines for ivacaftor therapy in the context ofCFTR genotype. Clin. Pharmacol. Ther. 95, 592–597 (2014).
37. Crews, K.R. et al. Clinical Pharmacogenetics ImplementationConsortium (CPIC) guidelines for codeine therapy in the context ofcytochrome P450 2D6 (CYP2D6) genotype. Clin. Pharmacol. Ther. 91,321–326 (2012).
38. Gammal, R.S. et al. Clinical Pharmacogenetics ImplementationConsortium (CPIC) guideline for UGT1A1 and atazanavir prescribing.Clin. Pharmacol. Ther. 99, 363–369 (2016).
39. Hicks, J.K. et al. Clinical Pharmacogenetics ImplementationConsortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypesand dosing of selective serotonin reuptake inhibitors. Clin.Pharmacol. Ther. 98, 127–134 (2015).
40. Hicks, J.K. et al. Clinical Pharmacogenetics ImplementationConsortium guideline for CYP2D6 and CYP2C19 genotypes anddosing of tricyclic antidepressants. Clin. Pharmacol. Ther. 93, 402–408 (2013).
41. Hoffman, J.M. et al. Developing knowledge resources to supportprecision medicine: principles from the Clinical PharmacogeneticsImplementation Consortium (CPIC). J. Am. Med. Inform. Assoc. 23,796–801 (2016).
42. Johnson, J.A. et al. Clinical Pharmacogenetics ImplementationConsortium Guidelines for CYP2C9 and VKORC1 genotypes andwarfarin dosing. Clin. Pharmacol. Ther. 90, 625–629 (2011).
43. Leckband, S.G. et al. Clinical Pharmacogenetics ImplementationConsortium guidelines for HLA-B genotype and carbamazepinedosing. Clin. Pharmacol. Ther. 94, 324–328 (2013).
44. Muir, A.J. et al. Clinical Pharmacogenetics ImplementationConsortium (CPIC) guidelines for IFNL3 (IL28B) genotype and PEGinterferon-a-based regimens. Clin. Pharmacol. Ther. 95, 141–146(2014).
45. Relling, M.V. et al. Clinical Pharmacogenetics ImplementationConsortium (CPIC) guidelines for rasburicase therapy in the context ofG6PD deficiency genotype. Clin. Pharmacol. Ther. 96, 169–174(2014).
46. Wilke, R.A. et al. The Clinical Pharmacogenomics ImplementationConsortium: CPIC guideline for SLCO1B1 and simvastatin-inducedmyopathy. Clin. Pharmacol. Ther. 92, 112–117 (2012).
47. Teng, K. et al. Cleveland Clinic’s Center for personalized healthcare:setting the stage for value-based care. Pharmacogenomics 15, 587–591 (2014).
48. Gottesman, O. et al. The CLIPMERGE PGx Program: clinicalimplementation of personalized medicine through electronic healthrecords and genomics-pharmacogenomics. Clin. Pharmacol. Ther. 94,214–217 (2013).
49. Overby, C.L. et al. Physician attitudes toward adopting genome-guided prescribing through clinical decision support. J. Pers. Med. 4,35–49 (2014).
50. Gottesman, O. et al. The Electronic Medical Records and Genomics(eMERG