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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. ([email protected])
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
1800
1700
1600
1500
1400
1300
1200
1100
1000
900
800
700
600
500
400
300
200
100
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
870 www.drugdiscoverytoday.com
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.
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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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