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Companion Diagnostics: Development,
Regulation and Compliance Considerations
This white paper outlines the necessary considerations for CDx
development; these include the impacts of regulatory and quality
compliance expectations in the US and European jurisdictions.
A Novella Clinical White Paper
Moving Potential. Forward.
Oncology Clinical
GlobalTrial
Oncology
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CRO
Companion Diagnostics: Development, Regulation and Compliance Considerations
Companion Diagnostics: Development,
Regulation and Compliance Considerations
Executive Summary
The underlying basis of personalised medicine
is the ability to select those individuals who
Companion Diagnostics
will benefit most from a given intervention. In
As a full service clinical research
its simplest form this requires two elements: a
organization (CRO) specializing
valid biomarker which determines treatment
in oncology and medical device
outcome for the individual and a reliable method
and diagnostics, Novella Clinical
for unambiguously determining the status of the
noted companion diagnostics
biomarker in the individual. Although there are
many variants in detail of this simple scheme, it
is this pairing between the intervention and the
selection method which drives the development
of a companion diagnostic test (CDx) for a
personalised medicine. This white paper outlines
becoming an increasing area of
interest for sponsors. We asked
one of Novella’s regulatory
consultants, Dr. Mark Richardson,
to explore the development of
companion diagnostics with a
particular focus on regulatory
the necessary considerations for CDx development;
and compliance expectations
these include the impacts of regulatory and quality
in both the US and Europe.
compliance expectations in the US and European
jurisdictions.
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©2012 Novella Clinical
Oncology Clinical Trial Operations
Companion Diagnostics: Development, Regulation and Compliance Considerations
CDx Context and Precedents
The requirement that medicines should be safe and effective inevitably moves us away from
the model of treating an undifferentiated patient population in which only a proportion will
derive the desired benefit and/or avoid the undesired risk. Our ability to identify the predisposing determinants of this proportion has accelerated the move and has truly enabled the
concept of personalising the treatment of individuals for the best possible outcomes. Personalised medicine is often described as the right treatment for the right person at the right time.
The term ‘personalised’ in this context refers to the ability to categorise a population of patients into sub-groups who respond differently to current treatment(s) and/or who may have
differing susceptibility to a specific disease. The impact of this principle on both clinical practice
and on the development of new drugs is considerable.
In the clinical setting, the incorporation of an additional test in the normal exercise of differential
diagnosis of patients with a given condition results
in the stratification or enrichment of the population
subset which can be considered either positively or
negatively for a particular treatment. The additional
diagnostic is therefore measuring a predictive biomarker of potential outcome which is specific to the
The use of the CDx with
the therapeutic product
allows the product’s benefits
to exceed its risks for the
population selected by
the CDx results.
particular treatment. This is distinct from a prognostic
biomarker which is an indicator of disease progress
or future severity and is unrelated to the effect of clinical intervention. In the development
of new drugs the opportunity therefore arises to screen for genotypes and phenotypes which
correlate with optimal drug response in animal models and early clinical trials. This information simultaneously enables the stratification of likely responder populations and provides
the data required to validate the corresponding biomarker as predictive for treatment effect.
Generally, this means that the use of the CDx with the therapeutic product allows the product’s
benefits to exceed its risks for the population selected by the CDx results.
The precedent example of a biomarker status used to determine treatment is the oncogene
product HER-2 which is over-expressed as a consequence of gene amplification in 25-30% of
breast cancer patients. These patients have a poorer prognosis than those whose tumours do
not over-express HER-2. Diagnosis of HER-2 overexpression is required for treatment with the
monoclonal antibody product Herceptin® (trastuzumab) approved by the FDA initially in 1998
(and shortly after in the EU) for the treatment of metastatic breast cancer, together with an
immunohistochemistry-based test kit called HercepTestTM (Dako, also approved in both jurisdictions); the first CDx. Subsequently approved tests use in situ DNA hybridisation of labelled
probes to detect the HER-2 gene amplification with fluorescence or chromogenic readouts.
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Oncology Clinical Trial Operations
Companion Diagnostics: Development, Regulation and Compliance Considerations
In another oncology setting the use of the monoclonal antibody product Vectibix® (panitumumab) for the treatment of colorectal cancer must only be used in patients with the wild type
K-RAS gene. The use of the corresponding CDx to select the responsive patient population
salvaged the approval of the product following the apparent failure to demonstrate sufficient
clinical benefit in an unstratified population. Post hoc analysis of the pivotal trial data demonstrated the wild type K-RAS component of the population showed superior progression-free
survival. It could be said that the CDx/biomarker combination retrospectively “saved” the
drug in this case. Coincidentally, it provided a valuable therapeutic option to a significant
number of patients in of a poorly served population which was otherwise “hidden” without
stratification by the CDx.
The FDA maintains an updated list of pharmacogenomic biomarkersi appearing in the labels
of approved drugs and biologics which require testing with a CDx. This clearly illustrates both
the rapid growth in, and the confirmation of the paradigm of personalised medicine.
Compliance Expectations for a CDx: Regulatory Principles
When results from a CDx are a determining factor in patient treatment, health care professionals must be able to rely on those results. Inadequate performance of a CDx could have
severe clinical consequences. A CDx might fail analytically (e.g., by not accurately measuring
the expression level of a protein of interest), or clinically (e.g., by not identifying those patients
at increased risk for a serious adverse effect). Consequently, an incorrect result could lead
to withholding effective therapy or to administering unsafe therapy. Therefore, the use of a
CDx with a therapeutic product raises important and legitimate
concerns about the safety and effectiveness of both the CDx
as a diagnostic and the drug as therapeutic product individually.
Because a CDx with inadequate “performance characteristics”
or other issues related to safety and effectiveness could expose
a patient to preventable treatment risks, regulatory compliance
standards should be used to assess the safety and effectiveness of
the CDx as used with the therapeutic when a therapeutic product
Inadequate
performance of a
CDx could have
severe clinical
consequences.
depends on the CDx for its safe and effective use.
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Oncology Clinical Trial Operations
Companion Diagnostics: Development, Regulation and Compliance Considerations
Compliance Expectation: Qualification and Validation of the CDx
The compliance standards of diagnostic performance should conform to the relevant national
and international general standards for clinical diagnostic and analytical method qualification
and validation. Specific aspects such as repeatability, reproducibility and precision estimates
should be evaluated. The diagnostic performance relates essentially to the evaluation of
sensitivity and specificity of the method. The principle elements in the validation of a novel
CDx were described in FDA draft1 concept paper in 2005iii.
1. Studies to show that test performance can be applied to expected clinical use as a
diagnostic with acceptable accuracy, precision, specificity and sensitivity: A demonstration of the device’s ability to accurately and reproducibly detect the analyte(s)
of interest at levels that challenge the analyte concentration specifications of the
device should be provided. (See number 3 below).
2. Sample requirements: All relevant criteria and information on sampling collection,
processing, handling and storage should be clearly outlined.
3. Analyte concentration specifications: It is recommended that, when appropriate,
a range of analyte concentrations that are measurable, detectable, or testable be
established for the assay.
4. Cut-off: It is recommended that there be a clear rationale to support an analytical
characterization of cut-off(s) value(s) which determine the positive and negative
threshold results.
Compliance Expectation: Clinical Utility of the CDx
After a new CDx has been analytically characterized, additional
studies should be performed to determine and validate clinical
utility. This addresses and quantifies the risks and benefits to the
patient associated with use of the test. It is the second element
of CDx compliance which requires the unambiguous demonstration of the ability of the test to result in patient selection that will
improve the benefit/risk of the drug in the selected and nonselected groups.
Optimally, these studies will be performed based on informa-
After a new CDx
has been analytically
characterized,
additional studies
should be performed
to determine and
validate clinical utility.
tion known from analytical studies and based on pilot studies
or careful analysis to determine relevant populations to be
studied to establish clinical test performance and target cut-off points in biological specimens.
Clinical utility testing can be conducted in one of two ways. First, the proposed final marketing
format CDx can be used for patient selection in the pivotal clinical trial(s) under the conditions of its future routine clinical use. Second, and more commonly, retained patient samples
This draft document has never been finalised or withdrawn (even though it is marked “not for implementation”).
Its technical contents remain seminal and are complemented by more recent FDA draft guidanceiii which
clarifies the regulatory pathway for approval of a CDx in concert with its corresponding drug.
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©2012 Novella Clinical
Oncology Clinical Trial Operations
Companion Diagnostics: Development, Regulation and Compliance Considerations
which had been tested during the trial(s) in a central lab are used, in
simple terms, to challenge the final format CDx to achieve the same
results. The second strategy is more attractive to regulators because
it removes the possibility of CDx usage variation influencing the data
on which the primary assessment of drug efficacy is made.
The assessment of clinical utility should also take into account operator
dependent subjective influences which might be significant outside of
the controlled environment of a central or reference clinical laboratory.
Although medical staff are highly trained, they may not all be experts
in the area of diagnostic testing, and so addressing human factors
and the workflow required of the user from sample collection to
... addressing human
factors and the workflow required of the
user from sample
collection to display
of the test result is
imperative for assuring
the clinical utility of
the CDx in routine use.
display of the test result is imperative for assuring the clinical utility
of the CDx in routine use. Data visualisation and interpretation are of
particular relevance here to ensure that the test result is not open to subjective influence and
consequent inconsistency between operators. The provision of specific training, instructional
materials, and access to “live” advice and/or follow up are likely to be necessary to this end.
Integration of CDx and Drug Development
With the greater emphasis in modern drug development on design rather than screening, it
is most usually the case that the pharmacological target is known at an early stage and well
characterised at the molecular level. It is therefore typical that the determinant of treatment
response, the predictive biomarker, is known long before clinical studies are initiated, and
probably before formal preclinical development studies start. If the biomarker is novel a new
test will be required. However the principles of CDx development also apply to a new version
of an existing diagnostic marketed by a different manufacturer, or to an existing diagnostic
that is already authorised for use in another indication or with a different drug.
If there is an existing diagnostic method for the identified biomarker then the burden of
method development and most of the analytical validation curriculum will be eliminated if the
method is already fit for purpose. This will depend on the extent of possible variables such as
sample collection, preparation and storage (and their compliance requirementsii), and analyte
variations between the ways in which the method is used.
When possible CDx for subsequent pivotal efficacy and/or safety studies should be developed
and analytically validated early in the drug development process to allow clinical test validation
and clinical test utility determination during the late stage clinical trials. Ideally, a new
diagnostic intended to inform the use of a new drug will be studied in parallel with early drug
development (preclinical, Phase I and possibly Phase II trials) and diagnostic development
will then have led to pre-specification of all key analytical and clinical utility aspects for the
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©2012 Novella Clinical
Oncology Clinical Trial Operations
Companion Diagnostics: Development, Regulation and Compliance Considerations
subsequent (late Phase 2 and Phase 3) pivotal clinical studies. These include the intended
population and selection of diagnostic cut-off points for the biomarker intended to delineate
test positives, test negatives, and, when appropriate, equivocal zones of decision making. This
principle is illustrated in the schematic shown in Figure 1.
Platform Change
Marker Assay
Validation
Prototype
Design or
Discovery
Basic
Research
Analytical Validation
Diagnostic Kit
Clinical Validation Diagnostic
Kit; Final Platform
Preclinical
Development
Clinical
Phase 1
Phase 2
Phase 3
FDA Filing/
Approval &
Launch
Figure 1. Model outline of the integration of CDx and drug, taken from early FDA
guidanceiii. The reference to “platform change” is to recognise that refinement
modifications may be made to the CDx format during its development.
Candidate biomarker
definition, target
selection &
preclinical studies
Analytical performance testing
Marketing clearance/
approval (CE-marking/
510(k)/PMA)
Investigational Status During
Clinical Development
Clinical validation
Clinical utility
A CDx used to make treatment decisions in a clinical trial of a therapeutic product will be considered to be investigational unless its use for this purpose is already approved or cleared (e.g.,
CD EM
ER A
/C or
BE
R
CD EM
ER A
/C or
BE
R
CA
N D
B/ IV
N rO
o
CA
N D
B/ IV
N rO
o
CA
N D
B/ IV
N rO
o
CD EM
ER A
/C or
BE
R
the use of an existing CDx). If a CDx is being used to make critical treatment decisions, such as
patient selection, treatment assignment, or treatment arm eligibility, it will generally be considered
Joint
Joint
Joint
a significant riskpre-clinical
device under US and EUpivotal
regulations because
it presents a potential for serious
pre-submission
meeting
meeting
meeting
risk to the health, safety, or welfare of the subject in the event of malfunction.
Rx
Dx
Rx
Dx
Rx
Dx
• In the US the manufacturer of the CDx will be required to comply with the investigational device exemption (IDE) regulations. If a CDx and a therapeutic product are to be
studied together to support their respective approvals, both can be studied in the same
clinical trial if
it is conducted
in a manner
that
meets both
the requirements of the IDE
Filling/approvals
Non-clinical
Clinical
Clinical
Clinical
Discovery
& launch
development
Phase I
Phase II
Phase III
regulations and
the investigational
new drug
(IND) regulations.
(MMA/NDA/BLA)
• In the EU, there is no formal regulatory system governing the use or investigation of an
in vitro diagnostic device in the context of a clinical trial of an investigational medicinal
product. However the proposed use of a diagnostic test to determine treatment decisions
in a clinical trial must be fully justified in submissions to the national competent
authorities for clinical trial approvals.
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©2012 Novella Clinical
Oncology Clinical Trial Operations
Companion Diagnostics: Development, Regulation and Compliance Considerations
Regulation of CDx as In Vitro Diagnostic Devices
The critical function of the CDx in determining treatment
decisions raises significant concerns about the safety and
effectiveness of the test and any device used to perform
that test. These safety concerns also have an influence on the
development of any therapeutic product, as the companion
diagnostic test will require regulatory clearance and will need
to be marketed at the same time the therapeutic is available.
The challenges to co-developing a CDx and its corresponding
drug are the two classes of product have different timelines
for their development and regulatory milestones, have
separate submission pathways, and are regulated by different competent authorities. Drug development is a lengthy
process of about 9-12 years which has a classical sequential
structure of preclinical studies, clinical exploratory and
confirmatory trials within a regulatory framework specific
to investigational medicinal products. Interaction with the
The challenges to
co-developing a CDx
and its corresponding
drug are the two
classes of product
that have different
timelines for their
development and
regulatory milestones,
have separate
submission pathways
and are regulated by
different competent
authorities.
regulators during this time is critical to maximise the chances
for product approval after submission of the NDA or BLA in the US or the MAA in the EU.
And of course the finer details of this summary view are very different between these two
principle regulatory jurisdictions.
Most importantly, the approval of diagnostic tests and the approval of drugs are administered and
overseen separately both in the US and the EU by different entities under very different rules.
US Framework
In the US, the FDA oversees therapeutic products (drugs and biologics) and IVDs but this is
within separate divisions of the Agency. Therapeutics are regulated by CDER or CBER and
IVDs are regulated by the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)
within the Centre for Devices and Radiological Health (CDRH).
FDA published a guidance document in July 2011iv which sets forth the principles of regulatory
oversight and procedural control applied during the development and authorisation of a CDx
and its partner drug. It is complementary to the technical and scientific guidance provided in
the 2005 draft concept paper. One of the key messages behind the document is that the therapeutic product absolutely depends on the use of the respective diagnostic test and that a lack
of test approval effectively equals lack of therapeutic product approval. This implies that the
diagnostic test must be developed in parallel with the drug and ideally validated at the same
Phase III clinical trial. Combined validation is critical in establishing the safe use of the drug
based on the companion diagnostic test result.
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©2012 Novella Clinical
Oncology Clinical Trial Operations
Companion Diagnostics: Development, Regulation and Compliance Considerations
EU Framework
In the EU all medicinal products are regulated by the EMA or the individual national competent
authorities. Oversight of medical devices, including diagnostics, is the responsibility of the
Notified Bodies for evaluation of conformity with quality standards in manufacture for CE marking
and of the individual national competent authorities for the evaluation of their clinical performance.
In the EU the CDx can be an investigational in vitro diagnostic device (IVDD) during the
development of the drug. However, it must be CE marked following review by a Notified Body
(under the terms of Directive 98/79/EC) to allow its sale and use on the market, which would
be the case once the drug product is launched following approval by the EMA or the national
competent authorities. Historically, there has been no cross-talk or collaboration between the
regulators of medicinal products and in vitro diagnostic devices, and no coordination of their
separate evaluation and compliance oversight activities.
The upcoming revision of the EU In Vitro Diagnostic Medical Devices Directive (98/79/EC)
will incorporate the risk based categorisation of a CDx as an in vitro diagnostic device. A CDx
used to make a treatment decision will be placed in Class C, the second highest of the four
risk categories. This class assignment is indicative of “high individual risk and/or moderate
public health risk,” and will determine the extent and rigour of the conformity assessment
conducted by the Notified Body which will award the CE mark and the scrutiny of the clinical
utility assessment by the National Competent Authority.
Just as has been the case in the US, the EU regulatory framework is having to adapt to the
coming together of the drug and (in vitro diagnostic) device development disciplines resulting from the progress of personalised medicine. A series of reflection papers have been
issued which present further recommendations to drug and device manufacturers for
considerationv,vi,vii,viii,ix.
Importance of Dialogue with Regulators
The complexity of the development of a CDx, particularly within a drug development programme,
clearly requires a high degree of coordinated planning across several functions, very possibly
in different organisations. The time and resource investment implications are considerable
for all concerned. Dialogue and consequent “buy-in” from regulators is therefore essential;
regulators expect and welcome this interaction. Coordination is also required to work with
different regulators, both geographically (for a multinational development programme) and
for therapeutics and diagnostics. A model scheme shown in Figure 2 illustrates plausible
timings for such interactions relative to the development timeline. It is clear that regulators
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©2012 Novella Clinical
Platform Change
Clinical Trial Operations
Marker Assay
Analytical Validation
Clinical Oncology
Validation Diagnostic
Diagnostic
Validation
Kit
Kit; Final
Platform and Compliance Considerations
Companion
Diagnostics:
Development,
Regulation
Prototype
Basic
FDA Filing/
Clinical
Preclinical
Approval &
Design or
have acknowledged
bridging required between the regulation of medicines
Research their role in the Development
Phase 1
Discovery
Phase 2
Phase 3
Launch
and diagnostic devices to enable personalised medicines. While it has been easier in the context
of the infrastructure of the FDA to bring CBER or CDER and CDRH together, it has also
become a matter of routine to bring together the EMA, the national competent authorities
and the Notified Bodies for Scientific Advice procedures in the EU.
Analytical performance testing
Clinical validation
Rx
Discovery
Dx
Non-clinical
development
Rx
Clinical
Phase I
Dx
Clinical
Phase II
CD EM
ER A
/C or
BE
R
CD EM
ER A
/C or
BE
R
Joint
pivotal
meeting
CA
N D
B/ IV
N rO
o
Joint
pre-clinical
meeting
Marketing clearance/
approval (CE-marking/
510(k)/PMA)
Clinical utility
CA
N D
B/ IV
N rO
o
CA
N D
B/ IV
N rO
o
CD EM
ER A
/C or
BE
R
Candidate biomarker
definition, target
selection &
preclinical studies
Joint
pre-submission
meeting
Rx
Clinical
Phase III
Dx
Filling/approvals
& launch
(MMA/NDA/BLA)
Figure 2. A schematic model of the relationship between the stages of a drug/CDx
development programme which shows suggested interactions with drug and device
regulators in the US (CBER/CDER and OIVD) and/or in the EU (EMA and Notified
Bodies/National Competent Authorities).
Conclusions
The need for personalised medicine has successfully brought together and fully integrated the
previously separate activities of drug and (in vitro diagnostic) device development. It is clear
that regulators have responded by recognising that there must be cross-talk between the corresponding regulatory disciplines to provide guidance and interactive support to sponsors in
this growing field. The early precedents, notably in oncology, and the subsequent accumulated
experience of regulators has informed the establishment of achievable compliance expectations which maximise the utility of a CDx while simultaneously ensuring its safe and appropriate use in treatment decision making.
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©2012 Novella Clinical
A Novella Clinical White Paper
About Novella Clinical
Novella Clinical, a Quintiles company, is a full service clinical research organization specializing
in supporting emerging oncology companies. Headquartered in Research Triangle Park, N.C.,
and Stevenage, UK, Novella is experienced in early, mid- and late-phase oncology trials and
provides the experience and insight to bring cancer medicines to market on time and on
budget. For more information, visit novellaclinical.com/oncology or contact us at 866-303-4966.
Mark Richardson PhD FTOPRA
Mark is an independent regulatory affairs consultant specialising in the development of small
molecule, biotech, biosimilar and advanced therapy products and is based near Oxford, UK.
Originally a molecular biologist, he has 25 years industry experience in the biotech, pharma
and CRO sectors in drug development and regulatory roles.
http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm
EMA Reflection Paper On Pharmacogenomic Samples, Testing And Data Handling, (EMEA/CHMP/PGxWP/201914/2006), 15 November 2007
iii
FDA Drug-diagnostic co-development concept paper, Draft April 2005
iv
FDA In vitro companion diagnostic devices, 14 July 2011
v
EMA Reflection paper on methodological issues associated with Pharmacogenomic biomarkers in relation to
clinical development and patient selection (EMA/446337/2011), Draft March 2011)
vi
EMA Reflection Paper On Pharmacogenomic Samples, Testing And Data Handling, (EMEA/CHMP/PGxWP/201914/2006), 15 November 2007
vii
EMEA Reflection paper on Pharmacogenomics in oncology (EMEA/CHMP/PGxWP/128435/2006), Draft April 2008
viii
EMA Reflection Paper on co-development of Pharmacogenomic biomarkers and assays in the context of drug
development (EMA/CHMP/641298/2008), Draft June 2010
ix
EMA Guideline on the use of pharmacogenetic methodologies in the pharmacokinetic evaluation of medicinal
products (EMA/CHMP/37646/2009), December 2011
x
Lawson et al. Activities to improve the regulatory framework for companion diagnostics step up. Regulatory
Affairs Medtech, November/December 2010, pp 4-7
i
ii
You see beyond the clinical trial. Your goal is to
ultimately give people a better quality of life and
more time to enjoy those special little moments.
Novella Clinical is proud to be a part of your mission.
Moving Potential. Forward.
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