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Drug Discovery Today � Volume 16, Numbers 19/20 �October 2011 REVIEWS

Pharmacogenomics: a new clinical orregulatory paradigm? Europeanexperiences of pharmacogenomics indrug regulation and regulatory initiativesKrishna Prasad and Alasdair Breckenridge

Medicines and Healthcare Products Regulatory Agency, 151 Buckingham Palace Road, London SW1 W 9SZ, UK

Are regulatory agencies and processes up to speed? This is an often asked question. Recent advances in

science and the improved knowledge of the human genome have a considerable influence on drug

development and their impact on the regulatory aspect is also significant for several reasons, including

changing stakeholder expectations and treatment paradigms. One of the challenges faced by the

regulators is the need to adapt regulatory processes to accommodate the newer methodologies and

techniques while ensuring that the biomarkers, tests and/or diagnostics, and the clinical trials are

appropriate and fit for purpose. The change in emphasis in pharmacological treatment from a

phenotype-based approach to newer methods is attractive but is it ready for universal adoption? This

paper details some of the regulatory responses to the developments in this area.

A recent Editorial in Nature Biotechnology claimed that ‘biomarkers

[were] on a roll’. The Editorial was referring to a collaborative

programme that identified biomarkers of renal damage [1]. The

editorial could apply to other markers. Of special interest are geno-

mic biomarkers and, therefore, pharmacogenomics (PGx) and phar-

macogenetics (PGt) are also receiving a great deal of attention across

the scientific community, from the general public and the media.

There appears to be a rapid progression and hightened anticipation

with regard to leading personalized healthcare to a new dimension

with the use of genomic biomarkers. Progress has been facilitated by

the detailed knowledge of the human genome and PGx is therefore a

reality for those ‘believers’. These discussions occupy many meet-

ings, conferences and even political campaigns, including the

introduction of the Personalized Medicine Bill in the US Congress.

With the rapid advances in technology, DNA analysis and sequen-

cing are tools no longer seen as the preserve of the ‘nerdy’ scientists

in Jurassic laboratories but something that is available to anyone

and everyone. One only has to glance at the number of media

programmes that glorify the value of DNA diagnosis in all manner of

situations to appreciate the impact this has on the general public.

Easy access to a variety of information on the Internet coupled with

direct to consumer (DTC) genetic tests has generated an intense

expectation that pharmacogenomics and pharmacogenetics can

Corresponding author:. Prasad, K. (Krishna.Prasad@mhra.gsi.gov.uk)

1359-6446/06/$ - see front matter. Crown Copyright � 2011 Published by Elsevier Ltd. All rights reserved. d

deliver the dream: the right drug and dose for the right patient,

and virtually eliminate adverse events.

The perception that genetics are infallible (i.e. DNA does not lie)

(Hubpages.com/hub/geneWize-Life-Sciences-Overview-DNA-

Does-Not-Lie) is extremely powerful and is likely to have been one

of the driving forces for the rise (i.e. a 500% increase over ten years)

in genetic testing labs (Fig. 1). This growth in testing labs is

dictated by business sense, an opportunity for venture capitalism

and the belief that those not benefitting most from the opportu-

nity will no longer remain venture capitalists. Therefore, it is easy

to believe that genomics and diagnostics appear to have moved

into a new paradigm and that a shift from the conventional to the

new definition of personalized healthcare has already occurred. All

that remains is for others (i.e. ‘non-believers’, doubters and gov-

ernments including policy makers) to keep pace. However, is this

true? As shown in Fig. 2, opinions differ [2].

Progress in PGt and PGx will depend on and involve Big Pharma,

academics, clinicians, regulatory agencies, health technology

assessment bodies, insurers and policy makers, none of whom

are immune to the intense pressure from the public, lobbyists or

think tanks [3–5]. For example, the policy briefing from the UK

Pharmacogenetics Study Group in July 2006 makes two significant

claims: (i) the pharmaceutical industry should, but might not, be

keen to drive the application of PGx to older products where

maximum public health gain is expected and (ii) regulators

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Tests: Growth of laboratory directory

Laboratories

Diseases for which testing is available

1900

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1700

1600

1500

1400

1300

1200

1100

1000

900

800

700

600

500

400

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01993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Data source: Gene tests database (2009) / www.genetests.org

Drug Discovery Today

FIGURE 1

The increase in the number of laboratories offering gene tests is significant and preceded the identification of the clear value of defining the genetic basis of many

diseases.

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(US and European) are slow in adapting to and adopting PGx or the

use of PGx tests to save lives and healthcare costs. In this context, it

is worth examining certain important questions. Has there been a

real paradigm shift? If so, how different should developments in

PGx be viewed from current regulatory standards or practises?

And, what level of evidence is needed for the adoption of PGx in

day-to-day practice? A discussion on the European regulatory

initiatives in the area of PGt/PGx will inevitably follow.

Is there truly a paradigm shift?Over the past century, pharmacological treatment of disease (or

symptoms) has progressed from an empirical basis to more-struc-

tured, evidence-based algorithms. Initially, they were dictated by

the prevailing understanding of the pathophysiology of the ail-

Drug Discovery Today

FIGURE 2

Are we ready for prime-time pharmacogenomics? This is a question posed by

many stakeholders and the answers might differ.

868 www.drugdiscoverytoday.com

ment (i.e. symptom) or the underlying disease. Early in the 20th

century the need for and choice of antibiotic treatment for an

infection was dictated by the symptoms in the first instance, and

isolates of the infectious agent subsequently. As the prevalence of

coronary artery disease increased (with a change in economic

circumstances), patients were grouped based on either symptoms

(angina, dyspnoea) or phenotypical characteristics (biomarkers)

such as lipid levels (LDL-C, triglycerides), highlighting the use of

shared common characteristics as unifying parameters for strati-

fication (grouping). Similarly, in oncology, for several years, the

interventions were based on the morphological and histopatho-

logical characteristics of the malignancy in question, with combi-

nation treatments targeting multiple pathophysiological

processes. Thus, treatments were personalized and individualized

using particular features (clinical and individual), albeit rather

unsophisticatedly in current PGx terms. Therefore, a personalized

approach to clinical medicine has been in existence for several

years but has been based on phenotypes. Interestingly, the knowl-

edge that inherited characteristics influenced response to inter-

vention was understood from historical times (e.g. favism and the

story of Pythagoras, 6th century BC), but progressed gradually

through the recognition of drug-induced haemolysis and G6PD

deficiency (in the 1950s) [6,7] to the identification of specific

genetic defects such as Thiopurine methyltransferase (TPMT)

polymorphism [8] in more recent times (during the 1980s). It

has long since been recognized that efficacy of intervention is

also variable as noted by an English surgeon, Stanley Boyd [9],

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following George Beatson’s reports [10] in Lancet (1897) regarding

the relationship between oophorectomy and breast cancer. These

observations provided the impetus for trials of hormonal treatments

using tamoxifen or aromatase inhibitors as adjuvant therapy in

breast cancer, but the sample size needed to be increased dramati-

cally from Boyd’s 15 cases. The variability of response encouraged

and necessitated design of specific clinical trials. In 1987, the

identification and recognition of HER-2 receptor expression in

breast cancer [11] and its greater prognostic value led to the sub-

sequent development of trastuzumab using targeted trials. One

could argue that this was probably the big turning point in the

application of PGt to patient selection for efficacy rather than safety

(i.e. excluding certain subjects for reasons of predicted lack of

efficacy based on the mechanism). The epidermal growth factor

receptor (EGFR) oncogene story had progressed in parallel for other

cancers with recognition of the tyrosine-kinase pathway and the

tyrosine-kinase inhibitor (TKI) class of antineoplastic agents, but at a

slightly slower pace. Understandably, completion of the human

genome project provided the much needed boost and further

acceleration. Clearly, the burden needed to support a proposed

intervention has changed over time and is influenced by a multitude

of factors including the demand, the therapeutic area, scientific

progress, the anticipated public health impact and the level of

public interest. Since the market approval (in 1999 in the USA

and in 2000 in the EU) of Herceptin1 (trastuzumab) for the treat-

ment of metastatic breast cancer, the numbers of products appear-

ing on the regulatory horizon with PGx information relating to

patient stratification have increased somewhat exponentially. For

example, between 2000 and 2008 there were 33 oncology products

that included some form of PGx information in regulatory submis-

sions to the European Medicines Agency (EMA) [12]. A similar

increase is noted in the scientific advice sought by sponsors in

relation to PGx-based approaches in the development programmes

(Box 1) and/or inclusion of PGx information in the product litera-

ture. Overall, therefore, the change in approach to intervention

(personalization) has been finely tuned by progress in PGx.

The question then is: notwithstanding such progress, why is

adoption of this exciting field apparently slow? If indeed it is slow,

it is worth examining the potential reasons and some of these are

detailed by Shurin and Nable [3]. The striking feature of these

developments is the time lapse of nearly four decades between the

first recognition of the inherited nature of drug-induced haemo-

lysis in G6PD deficiency and the first approved clinical use of PGx

information (i.e. the approval of Herceptin1). As the Editorial in

Nature Biotechnology [1] argues: a major part of this lag was caused

BOX 1

Increasing PGx-related regulatory work

Scientific advice process� Significant increase in PGx content of applications for advice� >25% of oncology-related products

CHMP/MAA applications� Between Jan 2000 and Dec 2008; 33 oncology products authorized� 9 (27%) had PGx-related information in product labels

� Several pharmacovigilance-related activities (CBZ, irinotecan,

atamoxetine, among others)

by the haphazard, ill-coordinated biomarker research and devel-

opment at the time. Included in this are: (i) a lack of an accepted

scientific framework for interpretation; (ii) a need for adequate

validation of test procedures and prospective validation studies;

(iii) the failure of efficacy or development of toxicity rarely char-

acterized in PGt terms and; (iv) whether the trials (including

hypotheses, designs, samples sizes and results or outcomes) are

adequate. A recent presentation by the Chairman of the Commit-

tee for Medicinal Products for Human Use (CHMP) highlights the

fact that there were ‘a lot of post hoc analyses’ [13] and the marker

status of subjects in pivotal trials was not measured for �50% of

the subjects in certain applications for marketing authorization

[14].

Are current clinical trials fit for purpose for PGx andbiomarker development?As with a personalized approach to medicine, Avicenna’s ‘The

Canon of Medicine of 1025’ detailed the rules and requirements of

clinical trials. Despite this, experiences have dictated the need for

regulatory oversight of development programmes and clinical

trials before a medicinal product is accepted for clinical use.

Thalidomide presented one of the worst examples of an inade-

quately studied agent, resulting in a legal basis for regulatory

frameworks being established. The Drug Amendments Act of

1962 by the US Congress, the Medicines Act in the UK [15] and

Directives by the European Economic Community [16] necessi-

tated the need for sophisticated clinical trials for demonstrating

the safety and efficacy of a new medicine in the modern era. As

treatment options for a particular disease increase, so does the

complexity of the trial needed with the endpoints (e.g. mortality)

dictating the duration and the sample size. Despite the increase in

the number and complexity of trials, nearly 40 drugs (medicinal

products) have been withdrawn from the market during the past

20 years, either owing to unrecognized risk for adverse events (e.g.

cerivastatin [17] and mibefradil (http://www.fda.gov/medwatch/

safety/1998/posicor.htm)) or because of inadequate evaluation of

the ‘at risk’ population (e.g. Vioxx1). Therefore if, by definition,

personalized medicine is aiming at smaller trials or sample sizes,

there is a possibility that many of the available trials investigating

genomic biomarkers might fall short of the evident burden needed

to fulfil regulatory demands. The trials evaluating geftinib exem-

plify this; only the pooled analysis of the three trials could provide

an adequate link between EGFR mutation status and outcome

owing to limitations of each of the three trials individually [18].

The design of the trial needs to be chosen carefully to maximize

the information from each trial and this has been the drawback in

several situations. In investigating Pharmacogenomic (PGx) bio-

markers, prospective trials that note only establish the use of the

medicinal product but also validate the biomarker in one attempt

are the ideal choice. The debate as to choice of the trial design that

best supports the investigation of pharmacogenomic component

for a new drugs and which suits the older established drugs is one

of the areas that has contributed to slower progress in the adoption

of pharmacogenomics into clinical practice as the same trial might

not serve both purposes equally well. Some examples have worked

well, such as the enriched design trials used for the development of

trastuzumab or the modified hybrid design of the Predict trial with

abacavir, but for specific reasons. These reasons include a high

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biological plausibility of the link between the marker and the

event (e.g. HER-2 overexpression and prognosis) and the mar-

ker–treatment–clinical-event interaction (e.g. abacavir) that were

prospectively evaluated. Although it is tempting to use the tar-

geted and enriched design studies to reduce sample size, such

studies suffer from certain disadvantages: they do not validate the

PGx biomarker and can overestimate the effect size that subse-

quent trials might be unable to replicate. One good example that

highlights many of difficulties with PGx adoption relates to war-

farin, despite the enthusiasm and importance of the cytochrome

P450 (CYP)2C9 and vitamin K epoxide reductase complex subunit

1 (VKORC1) polymorphisms. The reasons for this included diffi-

culty in evaluating the initial dose and then the maintenance

dose, inadvertent selection of subjects who had achieved stable

doses and poor definition of endpoints. Moreover, there were few

prospective studies in an unselected population comparing PGx-

based dosing with one accepted clinical dosing algorithm.

Thus far, few PGx biomarkers have been identified by retro-

spective analyses, case control studies or genome-wide association

studies. In such situations, there is a regulatory (and scientific)

expectation that some of the following caveats are fulfilled: data

from well-conducted randomized controlled trials (RCTs), precau-

tion against selection bias (i.e. marker status should be known or

samples should be available for majority of the subjects), avail-

ability of a pre-specified analysis plan, high biological plausibility,

and replication of the strength of association between the marker,

clinical event and intervention by drug treatment. It is often said

that retrospective studies suffer from lack of clarity on these points

and also what might be called ‘winner’s curse’ arising because of

overestimation of the effect size (i.e. the value of the association is

less than that noted in the initial study). These observations also

apply to studies where the marker–treatment interaction was

evaluated as an exploratory endpoint. Not surprisingly, many

regulators prefer replicated, prospective evaluations of the geno-

mic biomarkers in relation to drug development and especially for

biomarkers that are related to efficacy (e.g. in case of panitumu-

mab and geftinib). Each of these highlight particular aspects of

biomarkers that were evaluated during RCTs as exploratory end-

points; in the case of panitumumab, the marker status was known

for the majority of subjects, whereas for gefitinib the EGFR muta-

tion status was only known for some of the subjects across the

three gefitinib trials. The European regulators in each case opted to

return a positive opinion for approval but this was tempered by a

conditional authorization and restriction of indication based on

pooled analysis. Other examples where PGx data have influenced

European regulatory decisions and been incorporated into the

BOX 2

A list of some of the products with PGx information thatfeature in the EU product literature

OncologyLeukaemia Imatinib, nilotinib, dasatinib, arsenic trioxide

Solid tumours Trastuzumab, cetuximab, erlotinib, lapatinib,

panitumumab, gefitinibHIV Maraviroc, abacavir

Others Carbamazepine, phenytoin, among others

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product literature or clinical practise are available (some of these

are listed in Box 2). Unsurprisingly, there are also situations where

data have not been considered sufficiently persuasive (irinotecan,

atomoxetine and warfarin). This brings us to a further set of crucial

points: (i) how to establish the predictive value of a PGx biomarker

or test including evaluation of sensitivity and specificity; (ii) how

best to integrate the diagnostic test development into drug devel-

opment; (iii) how to combine drug and diagnostic device regula-

tion; and, lastly, (iv) what and where are the current European

regulatory initiatives.

The European regulatory processPharmaceutical regulationThe pharmaceutical legislation in Europe has undergone consid-

erable progressive change since the Directive of 1965 (Directive 65/

65/EEC). The establishment of CPMP (now CHMP) as the main

advisory committee to the EC in 1975 (Directive 75/319/EEC) saw

the first effort at harmonization (i.e. mutual recognition of

approved products in member states). Subsequently, several steps

followed: EEC/2309/93 established the role of the EMA (formerly

the EMEA) in 1993 to facilitate a centralized authorization for

certain medicinal products across all member states, and Regula-

tion EC 726/2004, the council regulation on human medicines,

included additional procedures (decentralized procedure) in an

effort to harmonize the drug regulatory process further. It also

established the Coordination Group for Mutual Recognition and

Decentralized Procedures (human) [CMD(h)] as the group to dis-

cuss difficult issues. Both the Scientific Advice Working Party

(SAWP) and the Pharmacogenomics Working Party (PGxWP) pro-

vide opportunities for the sponsors and/or developers to seek

advice; a formal process with SAWP and an informal process with

the PGxWP. The latter offers a common forum for discussion with

the FDA and, on occasion, the Pharmaceuticals and Medical

Devices Agency (PMDA) in Japan.

One interesting aspect of European legislation is the distinction

between pharmaceutical legislation and that of the devices. The

latter are governed by legislation that is distinct from the phar-

maceutical legislation: directives governing the regulation of gen-

eral medical devices, implantable medical devices and in vitro

diagnostic devices (tests). Pharmaceutical legislation differs from

that covering devices and the remit of the EMA is limited to

regulation of medicines. For devices, the EU still retains the overall

responsibility but a centralized body (akin to the EMA) has not yet

been constituted. Device legislation empowers national compe-

tent authorities to regulate the devices within respective national

boundaries based on several directives (90/385/EEC; Medical Dev

Dir 93/42/EEC; and the IVD directive of 1998, 98/79/EC) and the

automatic mutual recognition in all member states of device

authorizations. The in vitro diagnostics (IVD) directive provides

for the Communaute Europeenne (CE) marking (i.e. self attesta-

tion or through notified bodies) for most diagnostic devices.

The IVD directive operates a list-based system with annexes that

define the regulatory oversight needed according to risk, and the

degree of intervention needed. National competent authorities

oversee the work of notified bodies and recommendations for CE

marking. Therefore, the companion diagnostics (classed as IVDs)

crucial to determine further intervention (immediate or delayed)

when linked with drug development or therapy are regulated

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BOX 3

Regulatory initiatives

Drug regulatory agency initiatives: EMA/CHMPi. Regulatory rethink� Revisit drug and biomarker development approaches

� Revisit level of regulatory support and involvement

ii. Scientific advice and protocol assistance� Formal scientific advice through SAWP

� Informal discussion & advice through PGxWP

iii. Develop and issue EU regulatory guidance (PGxWP led)� Paper on EU experience of PGx in oncology (released 2008)

� Paper on inclusion of PGx in PK/PD studies (released)� Paper on co-development of drugs/companion diagnostics

(public consultation ended November 2010)

� Paper on methodological issues relating to PGx biomarkers and

patient selection (due for release soon)

iv. Biomarker qualification procedure (2007)

v. Innovative medicines task force

Collaborative effortsi. EMA (PGxWP)/FDA joint discussion meetingsii. Joint VXDS submissions opportunities

National competent authoritiesi. Conference/symposia/think tank meetings� MISG forum on personalized medicine (MHRA led; 2009)

� MHRA/BIA conference on personalized medicine (2011)

Initiatives related to devices/diagnostics� EU White Paper on MDD directive

� EU public consultation on recast of IVD directive

� EU biomarker/diagnostics symposium

� AFFSAPS initiatives on diagnostics (2009)

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independently of pharmaceutical legislation and might not have

had the same requirements as drugs in terms of clinical validation

prior to CE marking and authorization.

Markers, tests and companion diagnosticsRecognizing that biomarkers suffer from variable predictability

and applicability in drug development or clinical use, the CHMP,

in collaboration with the SAWP and PGxWP, made efforts to

provide guidance for biomarker development – called the biomar-

ker qualification process. The aim was to establish the biomarker as

being fit for intended purpose. This includes establishing sensi-

tivity, specificity and the predictability of the biomarker with

analytical validity. When such a biomarker is further progressed

in terms of conversion to a commercial test, the remit passes from

the EMA to the medical device authorization process (CE mark-

ing). The IVD directive anticipates that the test, when offered,

should conform to the ACCE framework that includes key com-

ponents (such as analytical validity, clinical validity, clinical uti-

lity and ethical, legal or social implications) [19] of genetic testing.

Although these processes (drug and device developments) can

function in parallel or independently for simple diagnostics and

treatment of disease, when an intervention or drug treatment is

dependent on the biomarker status, and thus results of a commer-

cial test, an interminable link is established with an inherent risk

of, and consequences from, any misclassification. For example, a

diagnostic test for cystic fibrosis or muscular dystrophy could be

offered without an immediate planned intervention or drug treat-

ment. By contrast, in cases where the decision to use an agent is

dependent on the results of a test (e.g. HLA-B*5701 allele for

abacavir or CCR-5 trophic virus for maraviroc) any misclassifica-

tion owing to poor performance of the biomarker or the test has

serious consequences in terms of cost and public health. It there-

fore becomes important to establish the predictability of the

biomarker first in the clinical condition in line with the ACCE

framework and then a similar process for the commercial test(s).

When there are multiple laboratories involved or many commer-

cial tests are available, analytical validity of the assay used for each

test as well as concordance with the original assay become crucial

for drug developers, drug regulatory agencies and healthcare

providers. Although 100% concordance is ideal, achieving this

is not always feasible as in the case with HercepTest1 prior to the

use of trastuzumab (HercepTest1, instruction for use [20]).

There is yet another facet to this interesting issue from a

regulatory angle: is there a need to mention a specific commercial

test in the product label for the drug? Such a question raises two

main issues. The inclusion might imply that the test or assay is

endorsed (by the regulators and the pharma company) and there-

fore have financial consequences for the companies involved and

for care providers. By contrast, if the commercial test was not used

in the clinical trials during development but is offered as an

alternative (e.g. HercepTest1), concordance with the original

assay assumes greater significance. The risk of misclassification

leading to the possibility of offering an inappropriate treatment

has serious consequences for all concerned including care provi-

ders, the industry (financial liabilities) and, most crucially, the

patients. These are important aspects that need further discussion

in regulatory terms. The European medicine regulators (CHMP

and national competent authorities) have, so far, refrained from

the inclusion of specific tests in drug labels (i.e. product informa-

tion) until a consensus on regulation of companion diagnostics

can be reached and the EU’s consultation on the recast of the

devices directives should provide some direction.

Regulatory initiatives to further PGx in EuropeIt is obvious that there are hurdles to jump in making PGx a

working reality, both in Europe and worldwide. As detailed above,

these include scientific, regulatory, financial and commercial

issues. The first two have a level of overlap and, at the European

level, various initiatives are under way (Box 3). The initiatives are

aimed at not only facilitating progress of PGt and biomarker

development but also addressing the issues relating to the devel-

opment of PGx tests (companion diagnostics).

The initiatives listed are ongoing in addition to those promoted

by IMI initiatives and funding calls including FP7 and anticipated

FP8 programmes. The EMA and the National Competent Author-

ity led initiatives are aimed at improving the process of biomarker

development and issuing guidance on debatable topics to achieve

clarity. The biomarker qualification process has been created to

provide industrial sponsors with the opportunity to establish

whether the biomarkers (genomic or otherwise) are fit for

the intended purpose in a regulatory context. Biomarkers of

renal injury are a prime example of a success story of collaborative

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FIGURE 3

Certain processes might start slowly but momentum, once gained, can

become inexorable.

872 www.drugdiscoverytoday.com

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efforts between industry and regulatory agencies. The guidance

documents are self explanatory and address specific questions

that are often raised by the industry (both pharma and diagnos-

tics) related to the development programmes and when and

where companion diagnostic tests are essential. The papers also

provide a view of the current regulatory thinking on requirements

for diagnostics from a drug regulatory view point. It is expected

that, although these are currently non-binding stipulations, they

will enhance discussions and arrive at a consensus of opinion. The

initiatives also include and confirm the efforts at harmonization

of requirements between various regulatory agencies. These are

exemplified by the collaborative discussions between EMA, FDA

and PMDA for PGx in drug development but also between EU

member states regarding the state of IVD directive. Although it is

impossible to gaze into a crystal ball and predict the outcome of

several the initiatives, the message is clear – watch this space.

Regulators are moving toward a common goal. Often, such move-

ment might start slowly but, once momentum is gained, it could

become inexorable (Fig. 3).

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