News & Views

ISSN 1462-241610.2217/PGS.13.73 © 2013 Future Medicine Ltd Pharmacogenomics (2013) 14(8), 861–867 861

part of

861

The Wolfson Centre for Personalised Medicine (WCPM) [101] was established in 2009 through joint investment by the Wolfson Foundation and The University of Liverpool (UoL). The Centre is housed in a Grade II listed building designed in 1887 by Alfred Waterhouse, a famous British architect, associated with Victorian Gothic Revival architecture. His most notable work being the Natural History Museum (London, UK).

The Centre is integral to the Depart-ment of Molecular and Clinical Phar-macology at the UoL, which also hosts the Medical Research Council (MRC) Centre for Drug Safety Science (CDSS) [102]. The two centers undertake funda-mental basic and clinical research into the causes, characteristics and consequences of drug efficacy and toxicity, aiming to improving the benefit:risk ratio of drugs through improved drug design and drug and patient selection. The WCPM cur-rently employs 73 scientists, medics, research nurses and administrators, who are largely funded through research grants from governmental organizations (Department of Health, National Insti-tute of Health Research (NIHR), MRC, Wellcome Trust, European Commission) and charities (Epilepsy Research UK among others).

Crucial to the WCPM research strategy is the ‘bench to bedside’ concept, whereby the discovery of a biomarker associated with variable drug response is taken on a

long journey to its clinical implementation and assessment of its impact on population health [1]. Although biomarker discovery still heavily dominates the field of phar-macogenomics and personalized medicine, the Centre is paving the way to assessing the clinical utility of pharmacogenetic test-ing and investigating clinical outcomes of interventions in targeted patient popula-tions. This is important for drug efficacy where response rates vary widely among patients, leading to unnecessary and waste-ful therapies with consequences to patient health and economic wealth. This is also true for adverse drug reactions (ADRs) where there is a need to understand the mechanistic reasons for drug toxicity and also to develop better biomarkers that can aid the stratification of individuals sus-ceptible to such toxicity, as well as develop intervention strategies that can help man-age such individuals. Here we describe examples of our orchestrated efforts to incorporate clinical and basic research, training of clinicians and scientists, pub-lic engagement and regulatory authorities’ involvement with the aim of facilitating implementation of personalized medicine into clinical practice.

Translation of a biomarker into clinical practice can be broadly divided into four translational phases: T1: discovery phase; T2: clinical validity/utility; T3: imple-mentation; and T4: assessing the effect of testing on public health [1]. WCPM has an interest in the identification of

Institutional Profile

The Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UKThe Wolfson Centre for Personalised Medicine is part of the Institute of Translational Medicine at the University of Liverpool (Liverpool, UK). It houses a multidisciplinary team of personalized medicine researchers engaged in collaborative research with partners across the globe. The primary focus of the centre is the identification of predictive biomarkers of drug safety and efficacy with the aim of translation from ‘bench-to-bedside’. Studies utilizing the latest genotyping and phenotyping, and point-of-care technologies, are undertaken with the ultimate aim of developing easy access for patients to truly personalized medicine. In addition to translation into clinical practice, the Centre puts significant emphasis into education of clinicians and scientists alike, as well as public engagement activities to promote personalized medicine.

Ana Alfirevic1, Daniel F Carr1, Fabio Miyajima1, Sudeep Pushpakom1, Laura Sutton2, Andrea L Jorgensen2 & Munir Pirmohamed*1

1Department of Molecular & Clinical Pharmacology, University of Liverpool, Block A: Waterhouse Buildings, 1–5 Brownlow Street, Liverpool, L69 3GL, UK 2Department of Biostatistics, The University of Liverpool, Shelley’s Cottage, Brownlow Street, Liverpool, L69 3GS, UK *Author for correspondence: Tel.: +44 151 794 5549 Fax: +44 151 794 5540 munirp@liv.ac.uk

Pharmacogenomics (2013) 14(8)862 future science group

News & Views – Institutional Profile

both genetic and nongenetic biomark-ers of drug safety and efficacy and their clinical utility.

Biomarker discovery�� Drug safety

Of particular interest is identification of predictive genetic biomarkers for predispo-sition to ADRs. In recent years the WCPM has identified strong associations between genetic biomarkers and predisposition to ADRs (Table 1). Collaboration with bio-technology and academic partners is now aimed at developing simple, reliable com-panion genotyping diagnostics with the ultimate aim of translation into clinical practice (Figure 1).

ADR biomarker identif ication can be aided by deep, accurate standardized phenotyping of patients. The WCPM has had a key role in the preparation of international standardization guidelines for three important ADRs: skin injury [2], liver injury [3] and torsades de pointes [4].

As the coordinating center for the Inter-national Consortium of Drug Hyper-sensitivity (ITCH), part of the Interna-tional Serious Adverse Event Consortium (iSAEC) [103], and the repository for DNA from worldwide sufferers of severe drug-induced skin injury, we are well placed to further elucidate the genetic basis of drug hypersensitivity. Understanding the mechanisms of drug hypersensitiv-ity is important and collaboration with the MRC CDSS has led to the develop-ment of a DNA archive in 400 volunteers, HLA-typed and linked to a cell archive, allowing the investigation of the HLA-restriction, which underlies many of these severe immune mediated reactions [5]. Drug-induced liver injury (DILI) is a leading cause of liver failure requiring liver transplantation. The WCPM has par-ticipated in a number of consortia-based projects such as DILIGEN, which led to the identification of HLA-predisposing factors for flucloxacillin and co-amoxiclav. The €32.4 million Innovative Medicines Initiative Project to develop mechanism-based integrated systems for prediction of DILI (MIP-DILI) [104] is a multidis-ciplinary consortium led by the MRC CDSS including key opinion leaders from academia (nine partners), biotechnology (six) and pharmaceutical industry (11).

Consistent with the underlying WCPM aim of undertaking translational research, we have developed a program on the cardio-vascular and/or metabolic safety of drugs, such as antiretrovirals. The work under-taken on HIV utilizes in vitro and in vivo disease models, which are interrogated in parallel by multiple omic approaches. A similar strategy has been employed for bio-marker discovery and mechanistic valida-tion to explain antiretroviral drug-induced adipose and renal toxicity.

The WCPM is a major hub for a GB£2.4 million MRC Programme Grant on nosocomial infection, focusing on establishing approaches for investigating host–pathogen interactions during Clos-tridium difficile infection, a severe diar-rheal condition associated with bacterial resistance to antibiotics. Using prospec-tively recruited patients, the WCPM aims to identify and validate host–pathogen biomarkers predictive of outcomes such as disease severity and prolonged hospital-ization, which significantly impact health and economics. The approach, combined with clinical and epidemiological infor-mation, supports the development of pre-dictive tools for early identification and intervention of at-risk patients. Candidate biomarkers include bacterial genomic sig-natures linked with pathogenicity to host immune response markers [6].

In addition to traditional recruitment and sample collection methods, we have also collaborated with the Clinical Practice Research Datalink (CPRD) [105] to utilize electronic medical records for identifica-tion of rare ADRs, such as statin-induced myopathy. Patients were identified from the CPRD database, which at the time consisted of 5 million patients from 688 participating primary care practices, and recruited directly by their own general prac-tice physician who also collected biological samples. This represents the first example of acquiring biological samples in associa-tion with CPRD – there were many chal-lenges identified, and solutions developed (to be reported in a future paper). This is important as this type of recruitment has enormous potential in aiding genetic bio-marker discovery and determining validity in rare ADR research.

As part of our multidisciplinary team, we have access to expertise in clinical trial

News & Views

www.futuremedicine.com 863future science group

News & Views Institutional Profile –

Tab

le 1

. Exa

mp

les

of

Wo

lfso

n C

entr

e fo

r Pe

rso

nal

ised

Med

icin

e st

ud

ies

focu

sed

on

bio

mar

ker

dis

cove

ry a

nd

clin

ical

uti

lity.

Dru

gIn

dic

atio

nPh

eno

typ

ePo

pu

lati

on

Fun

din

gD

escr

ipti

on

Dru

g s

afet

y

Car

bam

azep

ine

Epile

psy

Hyp

erse

nsiti

vity

Cau

casi

anD

oHH

LA-A

*31:

01 id

entifi

ed a

s pr

edic

tive

mar

ker

of m

ultip

le p

heno

type

s of

car

bam

azep

ine-

indu

ced

hype

rsen

sitiv

ity [13]

Nev

irapi

neH

IVH

yper

sens

itivi

tyM

alaw

ian

Wel

lcom

e Tr

ust

iSA

ECH

LA-C

*04:

01 id

entifi

ed a

s pr

edic

tive

mar

ker

of n

evira

pine

-indu

ced

Stev

ens–

John

son

synd

rom

e [14]

Fluc

loxa

cilli

nA

ntim

icro

bial

DIL

IC

auca

sian

DIL

IGEN

/iSA

ECA

s pa

rt o

f th

e D

ILIG

EN c

onso

rtiu

m, H

LA-B

*570

1 w

as id

entifi

ed a

s a

pred

ictiv

e m

arke

r of

fluc

loxa

cilli

n-in

duce

d he

pato

toxi

city

NSA

IDs

Ana

lges

ia/in

flam

mat

ion

Gas

troi

ntes

tinal

bl

eedi

ngM

ixed

NH

S C

hair

in

Phar

mac

ogen

etic

sM

ultic

ente

r tr

ial c

oord

inat

ed b

y th

e W

CPM

rec

ruiti

ng a

ppro

xim

atel

y 15

00

patie

nts

Inha

led

cort

icos

tero

idA

sthm

aA

dren

al s

uppr

essi

on:

(dim

inis

hed

cort

isol

pr

oduc

tion)

Mix

ed

pedi

atric

NH

S C

hair

in

Phar

mac

ogen

etic

sSt

udy

coor

dina

ted

from

Liv

erpo

ol A

lder

Hey

Chi

ldre

n’s

Hos

pita

l in

colla

bora

tion

with

the

NIH

R M

edic

ines

for

Chi

ldre

n Re

sear

ch

Net

wor

kSt

atin

sH

yper

chol

este

role

mia

Myo

path

yC

auca

sian

MRC

Clin

ical

res

earc

h pr

actic

e da

talin

k el

ectr

onic

med

ical

rec

ords

use

d to

id

entif

y st

atin

-indu

ced

myo

path

y fr

om a

UK

dat

abas

e of

>5

mill

ion

patie

nts

Dru

g e

ffica

cy

War

farin

Ant

icoa

gula

tion

Thro

mbo

embo

lism

Mix

ed (

UK

)EU

FP7

(EU

-PA

CT)

Dem

onst

ratio

n of

clin

ical

util

ity

of V

KORC

1 an

d C

YP2

C9

geno

type

-ba

sed

dosi

ng a

lgor

ithm

usi

ng p

oint

-of-

care

gen

etic

tes

ting

Clo

pido

grel

/asp

irin

Acu

te c

oron

ary

synd

rom

eA

ntip

late

let

resp

onse

Mix

ed (

UK

)N

HS

Cha

ir in

Ph

arm

acog

enet

ics

Mul

ticen

ter

obse

rvat

iona

l tria

l coo

rdin

ated

by

the

WC

PM

stud

y in

corp

orat

es u

se o

f su

rrog

ate

phen

otyp

e m

easu

res

of d

rug

resp

onse

suc

h as

pla

tele

t ag

greg

omet

ryA

ntie

pile

ptic

sEp

ileps

yRe

frac

tory

epi

leps

yC

auca

sian

EU F

P7 (

EURI

PID

ES)

Ex v

ivo

stud

ies

to id

entif

y m

echa

nism

s of

cel

lula

r m

ultid

rug

tran

spor

ter

func

tion

and

iden

tifica

tion

of c

ompo

unds

inhi

bitin

g dr

ug

tran

spor

t at

the

blo

od–b

rain

bar

rier

Ant

idep

ress

ants

Dep

ress

ion

Mod

erat

e-to

-sev

ere

depr

essi

onM

ixed

NIH

R-H

TAFo

lATE

D is

a r

ando

miz

ed c

ontr

olle

d tr

ial l

ooki

ng a

t th

e po

tent

ial

bene

fit o

f fo

lic a

cid

supp

lem

enta

tion

to a

ntid

epre

ssan

t th

erap

y.

WC

PM is

con

trib

utin

g to

the

stu

dy w

ith g

enet

ic a

na ly

sis

DIL

I: D

rug-

indu

ced

liver

inju

ry; D

oH: D

epar

tmen

t of

Hea

lth; H

TA: H

ealth

Tec

hnol

ogy

Ass

essm

ent;

iSA

EC: I

nter

natio

nal S

erio

us A

dver

se E

vent

Con

sort

ium

; MRC

: Med

ical

Res

earc

h C

ounc

il; N

HS:

Nat

iona

l Hea

lth S

ervi

ce;

WC

PM: W

olfs

on C

entr

e fo

r Pe

rson

alis

ed M

edic

ine.

Pharmacogenomics (2013) 14(8)864 future science group

News & Views – Institutional Profile

design, statistical genetics, bioinformatics and computational biology to ensure the most appropriate and up-to-date methods are applied to the design and ana lysis of studies. For computationally intensive work the department utilizes high-per-formance and high-throughput comput-ing facilities in which the WCPM and the wider UoL have made significant invest-ment. Access is also possible through the Northwest Grid Cluster, which has systems hosted in Daresbury, Lancaster, Liverpool and Manchester. In addition, the UoL also offers a high-throughput computing ser-vice in the form of a Condor pool, making widespead use of PCs across the university campus (up to 1400 cores).

�� Drug efficacyThe WCPM conducts a number of efficacy studies aimed at identifying genetic predic-tors of patient drug response (Table 1). Sev-eral independent and collaborative studies undertaken on the pharmacogenetics of the anticoagulant drug warfarin demon-strated the clinical utility of CYP2C9 and VKORC1 genotyping-based dosing algo-rithms [7] leading to the development of clinical guidelines.

The WCPM has played a key role in the NIHR Health Technology Assess-ment-funded FolATED study. This is a randomized controlled trial (RCT), where moderate to severely depressed patients

received 5 mg folic acid or placebo as adju-vant to their prescribed antidepressant. In a total of 440 patients, we are investigat-ing whether genetic polymorphisms in genes in the one-carbon folate metabolism and methionine synthesis pathways could be predictive markers for the efficacy of folic acid.

Drug treatment resistance is an impor-tant hurdle in many disease therapies including cardiovascular and CNS disease treatments. Our focus is on identification of factors leading to clinical resistance to drugs such as aspirin in acute coronary syndrome patients or in pregnant women at risk for preeclampsia. Additionally, refractory epilepsy has been investigated in the European Commission Seventh Framework Programme (EU FP7)-funded collaborative European project (EURIP-IDES) [106]. In collaboration with academ-ics from Australia and the USA we are also investigating genetic factors in methadone response variability in individuals treated for heroin addiction.

�� Use of emerging technologies for biomarker discoveryWith the cost of massively parallel sequenc-ing continuing to fall rapidly, we have uti-lized next-generation sequencing capabili-ties to identify rare genetic variants asso-ciated with drug toxicity and efficacy. In collaboration with the Centre for Genomic

Figure 1. Research network and academic collaborations: Wolfson Centre for Personalised Medicine.

News & Views

www.futuremedicine.com 865future science group

News & Views Institutional Profile –

Research, University of Liverpool and the US FDA National Center for Toxicological Research [107], we are undertaking whole-exome and whole-genome sequencing of ADR patients. Through this work we are testing the hypotheses that rare variants and noncoding variants contribute to com-plex phenotypes with a large effect size, beyond the contribution of nongenetic factors and common genetic variants.

Clinical validation of biomarkers & therapeutic interventionsTranslation of research from bench-to-bedside is integral to the approach employed by the WCPM. In order to do this, appropriate validation of evidence collected (biomarkers, interventions, dos-ing algorithms and so on) and ascertain-ment of clinical utility are essential. The hierarchy of evidence required for clini-cal validation and utility [8] range from expert opinions and observational studies to RCTs and meta-analyses; the WCPM is involved in all levels of evidence synthesis as this process invariably depends on the clinical context [9].

RCTs are considered to be the gold stan-dard for demonstrating the clinical valid-ity and utility of a particular biomarker or intervention. However, for personal-ized medicine, novel design RCTs may be necessary. For example, TAILoR [108] is a novel Phase IIb adaptive design clinical trial undertaken by the WCPM translating findings from an in vitro adipocyte model of antiretroviral-induced cardiometabolic toxicity. The trial has been designed in collaboration with the MRC North West Hub for Trials Methodology Research (NWHTMR) [109]. Clinical trials are time consuming and expensive, and thus novel designs such as this, as noted in the FDA draft guidance [110], are required to reduce trial cost and duration, and allow for decision making on whether to move to a Phase III trial or to discontinue at the stage of interim ana lysis.

Another trial being conducted as part of an EU Consortium is the EU-PACT trial. This focuses specifically on warfa-rin, in collaboration with Sweden – the trial utilizes a biomarker strategy design [10] to evaluate whether genotype-guided dosing improves the safety and efficacy of anticoagulation therapy over conventional

dosing. In the trial we are also testing the feasibility of a point-of-care device, which provides genotype information for three alleles in CYP2C9 and VKORC1 in approximately 2 h. The trial will be reported in late 2013.

Besides RCTs, the WCPM also under-takes case–control and prospective cohort studies. Outcome measures vary and include categorical, continuous and sur-vival outcomes, often adjusted for clinical and environmental factors. The studies are designed in collaboration with the Department of Biostatistics. The design of a study really does depend on the area being studied – thus, for example, for most serious adverse reactions a case–control design is the most efficient, which we have utilized in identifying HLA bio-markers associated with hypersensitivity reactions to abacavir and carbamazepine. Additionally, we undertake systematic reviews and meta-analyses with a particu-lar interest is the methodological quality of pharmacogenetic studies [11].

An important aspect of developing the evidence base for determining valid-ity and utility is the cost–effectiveness of the intervention. As part of studies per-formed in WCPM, we routinely collect data on healthcare utilization. A typical example is our work on abacavir hyper-sensitivity, where the demonstration of the cost–effectiveness of HLA-B*5701 geno-typing prior to prescription was key in facilitating clinical uptake in the UK.

Clinical implementationIt is well known that the process from dis-covery to implementation is long and ardu-ous – the figure of 17 years is often quoted. There are many barriers to implementation of novel biomarkers into clinical practice, which vary across different healthcare sys-tems. Common issues include consistency in evidence utilization, training and educa-tion, and public engagement.

We have recently argued that the evi-dence required for implementing genetic tests is higher than nongenetic tests [12]. An important issue here may be the lack of familiarity with genetic testing, which could be addressed through better edu-cation and training. For this reason, we are involved in both undergraduate and postgraduate training of scientists and

Pharmacogenomics (2013) 14(8)866 future science group

News & Views – Institutional Profile

clinicians. An important initiative is the FP7-sponsored Marie Curie Initial Train-ing Network in Pharmacogenomics [111] providing training and research experi-ence to early stage PhD and postdoctoral researchers across several European coun-tries including Germany, UK, Russia and Slovenia. We are also actively involved in training of clinical scientists – we run the MRC Clinical Pharmacology Training Scheme [112], training clinicians to PhD level with personalized (or stratif ied) medicine as a cross-cutting theme.

Clinical implementation of pharma-cogenomic biomarkers will not only require the active engagement of clini-cians but also patients and the public. Without acceptance of these approaches by patients, the process of implementation will be almost impossible. The WCPM fronts a university-wide initiative promot-ing interdisciplinary research in personal-ized approaches, which has allowed us to actively engage with researchers in differ-ent disciplines including arts and humani-ties, providing us with novel insights into barriers to implementation.

The WCPM recognizes the value of public engagement – we have been involved in a range of activities from speaking at schools and public events, such as science festivals; providing short-term placements for high school pupils; and actively engaging in patient–public involvement groups, particularly involv-ing those patients who have developed severe ADRs. A notable activity over the last 2 years has been the Y-touring theatre company, which led to the development of a play on pharmacogenetics and personal-ized medicine at the Royal Albert Hall (London, UK) [113] that was broadcast to

schoolchildren, medical students and at science festivals.

Public healthAs we move forward with implementa-tion of pharmacogenetic tests, it will be important to ensure that this has a positive impact on public health. This is an area that has been poorly researched. Our strat-egy is to use electronic healthcare records allowing the follow-up and assessment of patient outcomes in real-world clinical set-tings. To this end, we have been working with the UK CPRD, as well as secondary care informatics systems.

ConclusionThe WCPM is dedicated to the develop-ment of the science of pharmacogenomics and personalized medicine. It is staffed by a multidisciplinary team, which is important given the complexities of implementing any findings into clinical practice. We continue to develop new clinical areas utilizing the latest advances in genomics and other omic technolo-gies collaborating globally with the aim of moving medicine from our current empirical approach to one that is more precise and predictable.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the sub-ject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Highlights

� The Wolfson Centre for Personalised Medicine houses a multidisciplinary research group with the aim of improving the translation of pharmacogenetic biomarkers into the clinic.

� A comprehensive approach from bench-to-bedside to application and implementation is utilized in the areas of both drug safety and drug efficacy.

� We apply state-of-the-art genomic analytical platforms to personalized medicine, which is combined with the most relevant clinical study designs and analytic (statistical and bioinformatic) platforms.

� Numerous national and international collaborations have been established to facilitate high-quality research.

� There is training and education of scientists and clinicians at all levels, and patient and public engagement activities to promote personalized medicine.

News & Views

www.futuremedicine.com 867future science group

News & Views Institutional Profile –

References1 Pirmohamed M. Acceptance of biomarker-

based tests for application in clinical practice: criteria and obstacles. Clin. Pharmacol. Ther. 88(6), 862–866 (2010).

2 Pirmohamed M, Friedmann PS, Molokhia M et al. Phenotype standardization for immune-mediated drug-induced skin injury. Clin. Pharmacol. Ther. 89(6), 896–901 (2011).

3 Pirmohamed M, Aithal GP, Behr E, Daly A, Roden D. The phenotype standardization project: improving pharmacogenetic studies of serious adverse drug reactions. Clin. Pharmacol. Ther. 89(6), 784–785 (2011).

4 Behr ER, January C, Schulze-Bahr E et al. The International Serious Adverse Events Consortium (iSAEC) phenotype standardization project for drug-induced torsades de pointes. Eur. Heart J. doi:10.1093/eurheartj/ehs172 (2012) (Epub ahead of print).

5 Monshi MM, Faulkner L, Gibson A et al. Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury. Hepatology (Baltimore, MD) 57(2), 727–739 (2013).

6 He M, Miyajima F, Roberts P et al. Emergence and global spread of epidemic healthcare-associated Clostridium difficile. Nat. Genet. 45(1), 109–113 (2013).

7 Klein TE, Altman RB, Eriksson N et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N. Engl. J. Med. 360(8), 753–764 (2009).

8 Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. BMJ 323(7308), 334–336 (2001).

9 Rawlins M. De testimonio: on the evidence for decisions about the use of therapeutic interventions. Lancet 372(9656), 2152–2161 (2008).

10 Freidlin B, McShane LM, Korn EL. Randomized clinical trials with biomarkers: design issues. J. Natl Cancer Inst. 102(3), 152–160 (2010).

11 Jorgensen AL, Williamson PR. Methodological quality of pharmacogenetic studies: issues of concern. Stat. Med. 27(30), 6547–6569 (2008).

12 Pirmohamed M, Hughes DA. Pharmacogenetic tests: the need for a level playing field. Nat. Rev. Drug Discov. 12(1), 3–4 (2013).

13 McCormack M, Alfirevic A, Bourgeois S et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N. Engl. J. Med. 364(12), 1134–1143 (2011).

14 Carr DF, Chaponda M, Jorgensen AL et al. Association of human leukocyte antigen alleles and nevirapine hypersensitivity in a Malawian HIV-infected population. Clin. Infect. Dis. 56(9), 1330–1339 (2013).

�� Websites101 The Wolfson Centre for Personalised

Medicine. www.liv.ac.uk/pharmacogenetics/centre_for_personalised_medicine

102 MRC Centre for Drug Safety Science. www.liv.ac.uk/drug-safety/research

103 International Serious Adverse Events Consortium. www.saeconsortium.org

104 Mechanism Based Integrated Approaches to Drug Induced Liver Injury. www.mip-dili.eu

105 Clinical Practice Research Datalink. www.crpd.com

106 European Research initiative to develop Imaging Probes for early In-vivo Diagnosis and Evaluation of response to therapeutic Substances. www.euripides-europe.com/en/joint-research-project.php

107 US FDA National Center for Toxicological Research. www.fda.gov/AboutFDA/CentersOffices/OC/OfficeofScientificandMedicalPrograms/NCTR/default.htm

108 TAILoR trial website. https://mcrnctu.org.uk/Staging/Tailor/Home/Login

109 MRC North West Hub for Trials Methodology Research (NWHTMR). www.liv.ac.uk/nwhtmr

110 Guidance for Industry: investigational new drug applications (INDs) – determining whether human research studies can be conducted without an IND. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM229175.pdf

111 Marie Curie Initial training Network. www.ikp-stuttgart.de/content/language1/html/13119.asp

112 MRC Clinical Pharmacology Training Scheme. www.liv.ac.uk/north-west-england-mrc-fellowship-cpt

113 Y Touring Theatre Company. http://ytouring.myresourcecloud.net/component/tortags/tag/pharmacogenetics.html?Itemid=157