Regulatory Feature
Biomarker qualification: a first step towards companion
diagnostic development
Biomarker qualification can be a first step towards companion diagnostic development. The European
Medicines Agency already has a biomarker qualification process and the US Food and Drug Administration is
developing one itself. The two agencies should find a way to harmonise their respective processes and propose
clear incentives for companies seeking to use them, say Sabah Malek, Sylvie le Gledic and Anne Dupraz-Poiseau.
Biomarkers have become a necessary tool
during drug development, in both the pre-
clinical and clinical settings. Drug developers
use these tools to objectively measure and
evaluate normal biological processes,
pathogenic processes, or biological responses
to a therapeutic intervention1. Biomarkers are
utilised to stratify patient populations, support
efficacy claims, quantify drug benefit, identify
safety problems, measure toxicity and reduce
clinical uncertainty.
Along with the discovery and use of
biomarkers, advances in science are also
making it possible to provide tailored
treatments to patients – ie personalised
medicine, which aims to provide the right
treatment, to the right patient, at the right
dose and/or at the right time2. In some cases,
especially where the biomarker’s assistance is
required to make clinical decisions, companion
diagnostics (CDx) are being developed as a
test. Biomarkers are indicators of drug effect
(normal biological and pathogenic processes as
well as biological responses), whereas CDx are
a test or an assay, developed for the biomarker
measurement, to directly assist physicians in
making treatment decisions. Next generation
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sequencing, system biology and proteomics are
just some of the areas where innovation is
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occurring and making the development of
CDx more commonplace.
Like most areas of scientific innovation, the
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regulatory landscape surrounding biomarkers
has not caught up with the use. Regulators
would like to ensure that the results of an
assessment can be relied upon to have a
specific interpretation and application in drug
development and regulatory decision making.
Traditionally, biomarkers were validated
through scientific debate, consensus, and
standing the test of time3. Using this process,
it could take years for biomarkers to be
widely accepted by the scientific community.
Regulatory authorities have now realised the
benefit and need for an accelerated process
to enable advances in drug development and
expedite the availability of safe and effective
products4. In 2007, the US Food and Drug
Administration and European Medicines
Agency announced a joint biomarker
qualification review of seven nephrotoxicity
biomarkers. This flagship biomarker
12 November 2011 www.scripregulatoryaffairs.com © Informa UK Ltd 2011
submission, made by the Critical Path
Institute’s Predictive Safety Testing
Consortium, was reviewed between June
2007 and January 2008. The conclusion from
this pilot joint experience5 spurred the FDA
and EMA to release their own guidance
documents related to qualification of drug
development tools, which involves not only
traditional biomarkers, but also other
methodologies, such as imaging, to assist
with drug development. The goal of these
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qualification programmes is to be confident
that, once qualification has been granted,
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regulators and drug developers will not need
to reconfirm utility of this tool when used in
a similar manner, ie context for use.
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The EMA was the first of the two agencies
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to make a process available for companies or
consortiums to qualify novel methodologies for
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drug development by publishing guidance in
20086. The term “methodologies”, according to
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the EMA, encompasses biomarkers, imaging
methods, or other drug development tools.
Since then, three biomarkers have been
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qualified in the EU7. The FDA followed suit in
2010 by publishing its own guidance document8.
This guidance is still in draft form and, to date,
its finalisation has not been announced.
The EMA and FDA processes
The qualification process through the EMA is
done via either Committee for Medicinal
Products for Human Use (CHMP) qualification
advice or CHMP qualification opinion.
Depending on the available biomarker
supportive studies, it is either an opportunity to
receive guidance on the submitted plan for
future studies (biomarker qualification advice)
or to obtain a qualification opinion. The latter is
based on the review of final protocols, study
reports and supportive data to establish the
use of a defined novel methodology for a
specific purpose in drug development. The final
goal of both (qualification advice and opinion) is
to lead to a proposed innovative development
method (ie qualified biomarker) that is
considered an acceptable regulatory standard
for the claimed used in a defined context for
drug development. The specific EU qualification
process is described in further detail in Table 1.
The FDA’s qualification process is under the
responsibility of the agency’s Center for Drug
Evaluation and Research, which will evaluate the
submitter’s initial letter of intent (LOI) to make a
determination on whether or not continuation
of consultancy and advice is necessary. The LOI
contains a short summary of the drug
development tool, its proposed context of use,
a brief overview of the available data and a
summary of future studies planned. A positive
qualification will allow drug development tools to
be used by drug developers within regulatory
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submissions without reconsideration and
reconfirmation if used within the qualified
context. The specific US qualification process is
described in further detail in Table 1.
While the stated purposes of the EMA and
FDA guidance are very similar, the processes
recommended by the two agencies for
qualification differ (see Table 1).
The major differences between these two
processes are as follows:
• The EMA has separated qualification opinion
from qualification advice, allowing one process
to be public and the other to be confidential,
respectively. The FDA does not offer such an
option and once a qualification determination
is reached, this is made public for comments.
The FDA wants to make this information
public to encourage scientific innovation and
speed up the availability of safe and effective
products. To promote this idea, the FDA
recommends the creation of collaborative
groups to undertake the development of
these drug development tools and go
through this qualification process.
• The EMA guidance specifically encourages
submitters to apply in parallel to the FDA
and the EMA. The EMA specifies that both
agencies will then communicate and meet
with the applicant together – made possible
by a confidentiality agreement between the
FDA and the EMA – to maximise the
chance of scientific consensus. The FDA
draft guidance does not mention this
parallel qualification opinion.
• An essential difference is the fact that the
FDA does not specify that any fees are
associated with its qualification process,
whereas the EMA will charge sponsors
scientific advice and follow-up fees. These
fees are unfortunately not negligible and
can be burdensome on many sponsors
(see Table 1).
 Regulatory Feature

Table 1: Comparison of the European Medicines Agency and US Food and Drug Administration qualification
processes
European Medicines Agency US Food and Drug Administration
Scope Address innovative drug development methods and tools Identify new tools to aid in drug development. Help bring
(novel methodologies for a specific purpose in drug new products to the patients faster
development)
Purpose CHMP qualification opinion: Acceptability of the specific use Qualification process for drug development tools intended
of a defined novel methodology for a specific purpose in for use in multiple drug development programmes or
drug development therapeutic areas
or
CHMP qualification advice: Advice on future protocols and
studies planned for qualification purposes of an individual
methodology/tool

Approach Consultancy and collaboration between CHMP and Consultancy and collaboration between FDA and other
individual companies individuals or companies
Agency enforcement Voluntary basis Voluntary basis
Fees Full scientific advice fee (>€75,000 ($105,000)) & follow-up No cost

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advice fee (>€37,000). Usual 90% fee reduction for small
and medium-sized enterprises

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Qualification team Specialised group of experts appointed by the CHMP, named Creation of a specialised group named “qualification review
“qualification team”, led by a co-ordinator and composed of a team” composed of Center for Drug Evaluation and Research

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minimum of five members. The experts are identified based review staff from various relevant disciplines with expertise
on technology supporting the development of the novel appropriate to review of the submission
methodology
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or
Procedure Main steps of the procedure: Pre-qualification: voluntary exploration data submission to
1. Letter of Intent determine if drug development tool development is
2. Assignment of an EMA scientific administrator (initial worthwhile
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validation step) Main steps of the procedure:

3. Appointment of the co-ordinator and the qualification 1. Letter of Intent
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team 2. Drug development tool briefing package and initial meeting

4. Preparatory meeting 3. Drug development tool investigation and development
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5. Evaluation of data and discussions 4. Submission of a formal qualification package

6. List of questions sent to applicant 5. Review of qualification package. For more controversial
7. Scientific advice working party review qualification decisions, CDER may decide to hold public
8. CHMP adoption of qualification advice and discussion of discussions.
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qualification opinion 6. Qualification decision by CDER

9. Public consultation (six weeks/only for qualification 7. FDA will put the new determinations as a draft guidance
opinion) and will use comments to develop a final guidance
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10. Adoption of final CHMP qualification opinion No timelines are mentioned in the guidance document
Precise timelines are given in the guideline
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Public status Qualification opinion: Open to public (public consultation)
prior to final qualification, publicly available once qualified
Qualification advice: Confidential document
Output CHMP qualification opinion and scientific assessment
CHMP qualification advice on future protocols and studies to
be further performed for qualification purposes of a specific
tool/methodology
Public consultation is not systematic prior to qualification
(CDER may hold public discussions for controversial drug
development tools). Once qualification determination is
confirmed, it is made open systematically to the public
Statement for qualification: conclusion regarding the
adequacy of the submitted data to support the drug
development tool’s qualification and context of use

• Process timelines are not given in the FDA
guidance, whereas the precise number of
days is specified for each step in the EMA
guidance. The submitter is able to use these
timelines to plan for the biomarker and
drug development programmes when this
information is transparent.
• Finally, many definitions (ie qualification,
biomarker, etc) are provided by the FDA,
along with explanations for the purpose of
the draft guidance document (“Why CDER is
developing a Qualification Process”?). It would
have been interesting for the EMA and the
FDA to align the proposed definitions and
explanation in their guidances, if only for
harmonisation purposes.
Significance for diagnostic developers
The benefits of the biomarker measurement
during clinical studies are in some instances so
apparent that this biomarker measurement
during commercialisation of the targeted
therapy is needed for a safe and effective use
of the drug. In these cases, the further
development of a CDx becomes a necessity.
For both therapeutic and CDx developers,
there are many steps to be covered for the
CDx development (beyond the qualification of
the related biomarker), which are still unclear
(eg need for co-approval or not, when to

© Informa UK Ltd 2011 www.scripregulatoryaffairs.com November 2011 13

Regulatory Feature
introduce CDx in drug development/clinical
trial, labelling requirements, etc). Unfortunately,
neither the FDA nor the EMA offers much
support for these stakeholders currently to
bridge the biomarker qualification to CDx/
drug co-development.
The FDA does not attempt to make a
connection between biomarkers and CDx
development within its various guidance
documents. There is no mention of CDx in the
current draft guidance on qualification of drug
development tools or a reference to
biomarkers within their recently released
guidance document on CDx9.
In the most recent EMA reflection paper
related to pharmacogenomics biomarkers,
diagnostic tests are discussed but rather briefly,
with no detailed information. In addition, this
refection paper is limited to genetic biomarkers
and does not apply to all potential biomarkers.
However, it does at least recognise the value of
determining diagnostic performance and clinical
validity. Furthermore, it concludes with a brief
description of the development and use of
CDx during drug development10.
There are other developmental issues that
need to be addressed as CDx become
increasingly necessary. The first is that there are
no criteria that can be utilied to distinguish
when the development of a CDx is necessary.
Not all biomarkers will be further developed
as CDx, therefore it is important to be able to
make this distinction.
Since development of CDx and targeted
therapeutics involves both the in vitro
diagnostic and pharmaceutical industry, both
regulatory divisions will have to interact in
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order to ensure that safe and effective devices
are allowed on the market.
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For the FDA, harmonisation and interactions
between the divisions within the agency will
be easier given the fact that all the divisions
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dealing with these products are under the
responsibility of the FDA. There are, however,
other operational challenges that the FDA will
face given the differences between these
divisions. Some examples of these differences
are the binding/non-binding nature of certain
submissions and the development of
formalised procedures.
In Europe, harmonisation and interactions for
drug and CDx regulatory co-approvals will be a
major challenge. This is mostly due to the fact
that while the EMA reviews and approves
targeted therapeutics, the majority of IVD
technical files, including most CDxs, do not need
to be reviewed by any regulatory authority at
present time under In Vitro Diagnostics Directive
98/79/EC11. The CE marking of these IVDs that
allows the product to be marketed across
Europe is today under the responsibility of the
manufacturer (self-certification). The IVD
14 November 2011 www.scripregulatoryaffairs.com © Informa UK Ltd 2011
Directive is currently under revision and the IVD
classification will be reviewed. It is planned that,
among other new requirements, CDx technical
files will have to be reviewed by notified bodies,
the certification organisations that member state
national authorities designate to carry out one
or more of the conformity assessment
procedures described in the annexes of the
various medical device directives. This should
bring more robustness to CDx development
but it will not solve all issues related to the
needed interactions between drug and CDx
regulatory authorities.
Conclusion
Biomarkers have the potential to allow drug
development programmes to move forward at
a rapid pace, especially now that regulators
have taken steps to lay out the framework for
their qualification. As illustrated, there are
today well defined biomarker qualification
processes in the EU and in the US. The EMA
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guidance specifically encourages submitters to
apply in parallel to the FDA and the EMA.
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However, differences between both processes
might make that difficult, namely the lack of
harmonised definitions between both sides,
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the fees associated with the EMA process, the
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lack of timelines on the FDA side and the key
issue of data confidentiality and intellectual
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property. In the EU, nine biomarker
qualification requests were made in 2010,
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according to the EMA’s annual report12. Since
the flagship submission, however, the EMA has,
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to date, only qualified two other biomarkers.
For the FDA, the qualification process has
not yet been finalised or utilised. Despite this,
there are currently more than 100 drugs that
specify biomarkers on various sections of their
labelling (ie indications for use, dosage and
administration, boxed warning, etc). In fact, the
FDA has aggregated these drugs and published
this in a table on its website13. While the
biomarker qualification guidance is in line with
the FDA’s vision – to foster innovation – many
of those in industry will most likely prefer to
discuss qualification in connection with a
submission, which would be subject to
disclosure regulations. Many developers might
choose this option also because of intellectual
property issues, which can pose a disincentive
to enter the public qualification process with
the FDA. Therefore, to encourage the use of
the public qualification process, the FDA might
need to consider providing clarification on
what type of information it will make public in
order to protect intellectual property.
Academics might find the FDA and the
EMA biomarker qualification process helpful
during the discovery stage. However, these
institutions usually do not have resources to
handle these different and complex regulatory
processes. In addition, the fee associated with
the process in the EU is another barrier that
might discourage this process.
In general, to foster innovation and
encourage developers to utilise the biomarker
qualification process in the EU and US, it
would be beneficial to find a way to harmonise
both processes (from the EU and the US) and
to propose clear incentives. This would be key,
as biomarker qualification can be a first step
towards CDx development.
References
1. Biomarkers Definitions Working Group (2001),
Biomarkers and surrogate endpoints: Preferred
definitions and conceptual framework, Clinical
Pharmacology and Therapeutics, 69, 89-95
2. Lawson E, Lebon L et al, Activities to Improve the
Regulatory Framework for Companion Diagnostics
Step Up, Scrip Regulatory Affairs, 16 November 2010
3. Goodsaid F, Frueh F, Biomarker Qualification Pilot
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Process at the US Food and Drug Administration,
AAPS Journal, 2007, 9(1), E105-E108,
www.aapsj.org/view.asp?art=aapsj0901010
4. Goodsaid F, Frueh F, Strategic Paths for Biomarker
Qualification, Toxicology, 2008, 245, 219-223,
http://bit.ly/rM2vuK
5. EMA, Final Conclusions on the Pilot Joint EMEA/FDA
VXDS Experience on Qualification of
Nephrotoxicity Biomarkers, London, 22 January
2009, EMEA/679719/2008 Rev 1,
http://bit.ly/u5EJQG
6. EMA, Qualification of Novel Methodologies for Drug
Development: Guidance to Applicants,
22 January 2009, EMEA/CHMP/
SAWP/72894/2008,http://bit.ly/sXi5RJ
7. Qualification of novel methodologies and biomarkers,
EMA website, http://bit.ly/rzezt7
8. FDA, Draft guidance for industry, Qualification
Process for Drug Development Tools, October
2010, http://1.usa.gov/997GCf
9. FDA, Draft guidance for industry and FDA staff, In
Vitro Companion Diagnostic Devices, 14 July 2011,
http://1.usa.gov/mXrNZP
10. EMA reflection paper on methodological issues
associated with pharmacogenomic biomarkers in
relation to clinical development and patient
selection, 9 June 2011, EMA/446337/2011,
http://bit.ly/pFe9FR
11. Directive 98/79/EC of the European Parliament
and of the Council of 27 October 1998 on in vitro
diagnostic medical devices, OJ, 7 December1998,
L331, 1-37
12. EMA Annual Report 2010, 28 June 2011,
EMA/306870/2011, http://bit.ly/vggMiuf
13. Table of pharmacogenomic biomarkers in drug
labels, FDA website, http://1.usa.gov/uf7jlC
Sabah Malek, Sylvie le Gledic and Anne Dupraz-
Poiseau all work at Voisin Consulting Life Sciences,
whose main office is based in Boulogne, France, and
which specialises in regulatory strategy for healthcare
products. The authors would like to thank their
colleagues Mihaela MacNair and Patrick Larcier
for their contribution. Mrs Malek and Mrs MacNair
are based in the firm’s US office in Cambridge,
Massachusetts. Website: www.voisinconsulting.com.
Email: dupraz@voisinconsulting.com.