The 5th GCC in Barcelona (Spain) and 6th GCC in San Antonio (TX, USA) closed forums provided a unique opportunity for CRO leaders to openly share opinions and perspectives, and to agree upon recommendations on biomarker bioanalytical method validation.

1. White Paper
Special Focus Issue: Bioanalysis of biomarkers
Background
The GCC was formed in an effort to bring
together many senior level CRO representa-
tives to openly discuss bioanalysis and the
regulatory challenges, many of them exclusive
to the outsourcing industry. CROs are unique
in that they work with many different pharma-
ceutical companies and agencies, which results
in a unique and comprehensive perspective on
scientific approaches in relation to regulatory
requirements.
Since the formation of this international con-
sortium at the 1st GCC Closed Forum held on 14
September 2010 in Montreal, Canada [1], there
have been three meetings in North America [2,3]
and two meetings in Europe [4,5]. Furthermore,
GCC has published its official recommenda-
tions in White Papers [2,5,6], which were well
received within the bio­analytical arena, includ-
ing regulatory agencies, and an additional three
papers are presently in progress. In an effort to
accommodate the schedules of the CRO repre-
sentatives, GCC meetings will continue to be
tied to major conferences where attendance by
member companies is anticipated. More infor-
mation on the GCC unique structure can be
found in the publication titled ‘Formation of
a GCC’ [1].
Introduction
The 5th GCC Closed Forum was held on
13 November 2011 in Barcelona (Spain) and the
6th GCC Closed Forum was held on 27 April
2012 in San Antonio (TX, USA). A subgroup of
CROs highly specialized in biomarker analysis
has further expanded, discussed, reached con-
sensus and is now proposing a recommendation
on biomarker assay validations. The discussion
on this topic began at the 3rd GCC meeting
held in Guildford (UK) on 3 and 4 July 2011
where the challenges of biomarker assay vali-
dation were identified and the need to gener-
ate an official recommendation for the CRO
bioanalytical community was confirmed.
Biomarker validation
A survey was circulated to the GCC members
posing questions on the different approaches to
qualify or validate biomarker methods. The goal
was to be able to form a consensus on qualifica-
tion or validation of the methods. The results
of this survey on biomarkers are presented in
Table 1.
From the survey, it was found that the most
common reference documents used for bio-
marker qualification and validation are the
US FDA guidance [7], the European Medicines
Recommendations on biomarker bioanalytical
method validation by GCC
The 5th GCC in Barcelona (Spain) and 6th GCC in San Antonio (TX, USA) events provided a unique opportunity
for CRO leaders to openly share opinions and perspectives, and to agree upon recommendations on biomarker
bioanalytical method validation.
Richard Hougton1
, Dominique Gouty2
, John Allinson3
, Rachel Green1
, Mike Losauro2
, Steve
Lowes4
, Richard LeLacheur5
, Fabio Garofolo6
, Philippe Couerbe7
, Stéphane Bronner8
, Petra
Struwe9
, Christine Schiebl9
, Timothy Sangster10
, Colin Pattison10
, Rafiq Islam11
, Wei
Garofolo*12
, Maria Pawula13
, Mike Buonarati14
, Roger Hayes15
, Mark Cameron15
, Robert
Nicholson16
, Jake Harman16
, Jaap Wieling17
, Theo De Boer18
, Scott Reuschel19
, Laura
Cojocaru20
, Tammy Harter21
, Michele Malone22
& William Nowatzke22
Note: Due to the equality principles of Global CRO Council (GCC), the authors are presented in alphabetical order of company
name, with the exception of the first five authors who provided a major contribution to this paper.
*Author for correspondence: Global CRO Council (GCC), Toronto, Ontario, Canada
Tel.: +1 514 236 4225; E-mail: wei@global-cro-council.org; Website: www.global-cro-council.org
Author affiliations can be found at the end of this article.
2439ISSN 1757-6180Bioanalysis (2012) 4(20), 2439–244610.4155/BIO.12.197 © 2012 Future Science Ltd
For reprint orders, please contact reprints@future-science.com

2. Agency guideline [8], Lee et al. [9,10], Chau et al.
[11], Cummings et al. [12], Valentin et al. [13] and
Clinical and Laboratory Standards Institute
(CLSI) guidelines (formerly NCCLS) [101]. As
biomarkers are used more and more for deter-
mining subjects/patients safety, and biomarker
bioanalysis data are currently being submitted to
regulatory agencies, it is expected that guidance
for biomarker assessments will be included in
the upcoming revision of the FDA guidance for
method validation expected in 2012.
From the survey results and subsequent dis-
cussions, the majority of organizations apply a
‘fit-for-purpose’ approach to develop methods
Table 1. GCC survey on biomarker assays.
Question Europe North America
Does your organization apply
different definitions to biomarker
methods based on study end point
and what are they?
Yes: 75%; No: 25% Yes: 44%; No: 56%
Primary differentiation for bioanalysis: exploratory versus surrogate end point
Biomarker definitions: exploratory/research/safety/PD/proof-of-mechanism/primary and secondary
end point/stratification/companion diagnostic
When would your organization apply
a ‘fit-for-purpose’ qualification to a
biomarker method?
Regulated method not achievable: 37.5%
For everything: 37.5%
At sponsor’s request: 12.5%
Exploratory biomarkers: 12.5%
Regulated method not achievable: 18%
For everything: 36.5%
At sponsor’s request: 9%
Exploratory biomarkers: 36.5%
What parameters would you include
in a fit-for-purpose qualification of a
biomarker assay?
Ligand-binding assays
Calibration: 89%
Precision and accuracy†
: 89%
Selectivity/specificity: 78%
Parallelism: 67%
Storage stability: 67%
Sensitivity: 56%
Linearity of dilution: 44%
Recovery: 33%
Others: cross-reactivity, whole plate imprecision,
minimum required dilution evaluation
Clinical analyzers
Calibration: 88%
Precision and accuracy: 88%
Linearity of dilution: 63%
Storage stability: 50%
Selectivity/specificity: 38%
Parallelism: 38%
Recovery: 38%
Sensitivity: 25%
Kit parameters: 25%
Others: reference ranges (100–200 subjects),
cross-reactivity
Small molecules
Calibration: 100%
Precision and accuracy: 100%
Selectivity/specificity: 90%
Matrix effects: 70%
Parallelism: 30%
Storage stability: 70%
Sensitivity: 60%
Linearity of dilution: 40%
Recovery: 40%
Others: reference ranges, carryover
Ligand-binding assays
Calibration: 100%
Precision and accuracy†
: 100%
Selectivity/specificity: 100%
Parallelism: 60%
Storage stability: 80%
Sensitivity: 60%
Linearity of dilution: 60%
Recovery: 60%
Others: 20%; specificity/cross-reactivity,
minimum required dilution evaluation
Clinical analyzers
No reply from North America
Small molecules
Calibration: 100%
Precision and accuracy: 100%
Selectivity/specificity: 100%
Matrix effects: 50%
Parallelism: 25%
Storage stability: 100%
Sensitivity: 75%
Linearity of dilution: 0%
Recovery: 50%
Others: reference ranges, carryover
Do you set acceptance criteria before
or after the method ‘qualification/
validation’ for biomarker methods?
Before: 50%
After: 12.5%
Before and after: 37.5%
Before: 56%
After: 11%
Modified based on performance: 33%
A CRO stated that the acceptance criteria for QCs during sample analysis is statistically linked to
the performance of the method at validation using a confidence limit approach
†
Accuracy is not achievable for most biomarkers, only precision check.
CLSI: Clinical and Laboratory Standards Institute; EMA: European Medicines Agency; GxP: Good x practice; x can mean clinical, laboratory, manufacturing,
pharmaceutical and so forth.
White Paper | Global CRO Council for Bioanalysis (GCC)
Bioanalysis (2012) 4(20)2440 future science group

3. by establishing the expectations of the sponsor,
defining the scientific goal and the purpose of
the assay in terms of target values and accept-
ance limits, for example, defining the clinical
end point, and characterizing the performance
of the method during its development or using
the precision and accuracy results from valida-
tion to set the acceptance criteria for sample
analysis using a confidence limit approach.
The survey also showed that members use
surrogate matrices, surrogate analytes, standard
addition and/or other approaches to overcome
the inherent problem of endogenous levels for
biomarker assays. The different approaches each
have advantages and disadvantages, and selec-
tion depends on the assays’ intended use and the
availability of resources.
The consensus reached was that when there
is a definitive quantitative clinical end point,
the biomarker assay needs to be fully validated
and the acceptance criteria should be set based
on assay performance and the anticipated use;
Table 1. GCC survey on biomarker assays (cont.).
Question Europe North America
How do you apply acceptance
criteria to both ‘qualification/
validation’ of biomarker methods?
Ligand-binding assays
US FDA acceptance criteria: 57%
±20% and total error ±20%: 14%
Data reported with QC performance: 14%
Acceptance criteria based on requirement to
measure a particular PD change: 14%
Clinical analyzers
Meets kit performance: 50%
±15%: 17%
Data reported with QC performance: 17%
Acceptance criteria based on requirement to
measure a particular PD change: 17%
Small molecules
FDA (±15%): 63%
FDA (±20%): 13%
Data reported with QC performance: 13%
Acceptance criteria based on requirement to
measure a particular PD change: 13%
Ligand-binding assays
FDA acceptance criteria: 60%
±20% and total error ±20%: 20%
Acceptance criteria based on requirement to
measure a particular PD change: 20%
Clinical analyzers
Treated as any other large-molecule assay: 100%
Small molecules
FDA (±15% or as required): 40%
FDA (±20%): 20%
Acceptance criteria based on requirement to
measure a particular PD change: 40%
What claim of compliance is made
for a ‘fit-for-purpose’ qualification
of a biomarker method?
None: 87.5%
GxP or none: 12.5%
None: 89%
GxP or none: 11%
A CRO stated GLP, GCP or no compliance depending on the study – but would call it a ‘validation’
What claim of compliance is made
for the validation of a biomarker
method?
GxP: 25%
GLP: 37.5%
Non-regulated: 37.5%
GxP: 22%
GLP: 44%
Non-regulated: 34%
What industry reference documents
do you refer to for biomarker
‘qualification/validation’?
FDA guidance/EMA guideline [7,8]
Lee et al. (2006 and 2009) [9,10]
Chau et al. (2008) [11]
Cummings et al. (2010) [12]
Valentin et al. (2011) [13]
CLSI guidelines (formerly NCCLS) [101]
FDA guidance/EMA guideline [7,8]
Title 21, Part 58 (FDA GLP) [14]
Lee et al. (2006 and 2009) [9,10]
Nowatzke and Bowsher (2010) [15]
Other White Papers not detailed
For small-molecule biomarker
methods, do you use a surrogate
matrix, standard addition or some
other approach (other)?
Surrogate matrix: 40%
Standard addition: 30%
Surrogate analyte: 20%
Surrogate matrix: 50%
Standard addition: 25%
Surrogate analyte: 25%
How often do you apply relative
quantitative biomarker methods?
Rarely: 75%
Often: 25%
Rarely: 71%
Often: 29%
Does your organization segregate
biomarker work from regulated
bioanalysis and, if so, how is this
done?
Yes: 25%
No: 75%
A CRO stated that they have separate
departments: department of bioanalysis and
department of biopharmaceuticals and
biomarkers
Yes: 22%
No: 78%
A CRO stated they would consider considering a
change if appropriate for client needs
†
Accuracy is not achievable for most biomarkers, only precision check.
CLSI: Clinical and Laboratory Standards Institute; EMA: European Medicines Agency; GxP: Good x practice; x can mean clinical, laboratory, manufacturing,
pharmaceutical and so forth.
Recommendations on biomarker bioanalytical method validation | White Paper
www.future-science.com 2441future science group

4. for example, if determining a change in con-
centration of tenfold is all that is required, then
the FDA guidance [7] or European Medicines
Agency guideline [8] acceptance criteria may be
unnecessarily stringent for the purpose. When
there is a relative clinical end point, the bio-
marker assay could be validated using the ‘fit-
for-purpose’ approach (some laboratories term
this ‘qualification’). Although it was generally
acknowledged that the use of reference stand-
ards and the calculation of accuracy give the
data interpreter and regulators greater confi-
dence in the results of the method, for some
assays reference standards and calculation of
accuracy may not be necessary; for example, a
‘screening method’.
Screening and ‘qualified’ biomarker assays
are often fit-for-purpose and cost less than vali-
dated assays. If these tiers were used appropri-
ately, then biomarker assays may be used more
widely in the discovery phase.
The GCC members claim different regula-
tory compliance depending upon the degree
of qualification/validation, and also due to
the regulatory jurisdiction they exist within
(e.g., in the UK, GCP would apply regardless
of the use of the assay or validation status if
human samples are being analyzed). In general,
as well as a difference in the extent and level of
validation experiments due to regulatory impli-
cations, there are also implications with regard
to quality assurance involvement in the process
and documentation reviews/audits.
Currently, most members perform biomarker
analysis, including assays that are not validated,
alongside regulated bioanalysis, although some
would consider segregating the work if this was
required by their sponsors.
GCC recommendations
The GCC recommends three tiers of biomarker
bioanalytical method establishment:
n Validated;
n Qualified;
n Screening.
There is still clearly a difference of opinion in
what terminology laboratories use to define the
tier-level approach to biomarker assay valida-
tions. Given the use of the term ‘qualification’ in
the clinical biomarker arena, it would appear to
be a good idea to continue to strive for different
terminology to avoid ambiguity in laboratory
analysis of biomarkers and the tiered approach
to validation.
One of the major points to take into con-
sideration during method development is to
select the appropriate minimum required dilu-
tion (MRD). The assay platforms are similar
to the ones used for PK/TK assays; however,
the fundamental approach to determine the
MRD is opposite. The biomarker assay needs
to be able to detect endogenous level, therefore,
the QCs should include a matrix QC (blank)
diluted at the MRD as well as spiked QCs (care
needs to be taken if using a pooled matrix for
QCs due to the potential for analytical issues
– e.g., aggregation).
Overall, one of the typical errors found in
the validation of a biomarker is the dilution of
serum/plasma to a certain point to try to get a
good recovery of the spiked QCs. By doing so,
the sample results end up being all below the
LOQ during sample analysis. Therefore, the
first step should be to always run individuals
(normal individuals and disease population) to
ensure the correct MRD is chosen. This should
be done using parallelism experiments.
Table 2 presents the suggested requirements
for screening, qualified and validated biomarker
assays for ligand-binding assays as well as the
target acceptance criteria.
Clearly, at this point in time, there are no
regulatory guidance/guidelines for the valida-
tion of biomarker assays; only White Papers.
However, some of the White Papers have a large
representation of different and appropriate sci-
entific authors that have reviewed the experi-
mental requirements and gained a consensus.
Some have now been used fairly widely for
over 5 years (e.g., Lee et al.) [9]. Therefore, it is
recommended that when validating biomarker
assays, the spirit of the exercise should be based
on what is expected regulatory wise as labora-
tories have become accustomed to using regula-
tory guidance documents in the PK arena over
many years. However, due to the different uses
of the data (i.e., the clinical implications that
are not covered in PK guidance), specific bio-
marker White Papers, which contain the most
appropriate method to validate assays to ensure
they are appropriate for their intended use, are
recommended.
In addition, it should be considered that
the a priori approach is fine for validation,
if required, but setting criteria for sample
analysis based on the method performance
is still the most scientifically sound approach
White Paper | Global CRO Council for Bioanalysis (GCC)
Bioanalysis (2012) 4(20)2442 future science group

5. of controlling the assay in the production
phase. It should take into account end point
expectations as well as the knowledge of physi-
ological variability. This means that the target
acceptance criteria for sample analysis is also
set a priori but may be different from that of
the validation itself. This is also a sensible
approach as clinical and physio­logical infor-
mation are often lacking for novel biomarkers
and, therefore, a priori criteria for these are
often chosen without any really sound clinical
basis.
Box 1 shows the suggested minimum require-
ments for a qualified method with the option
of setting acceptance criteria based on the per-
formance of the assay during the qualification
process.
For ligand-binding and clinical analyzer
methods without a reference standard, some
sort of positive/negative control is required;
Table 2. Suggested requirements for screening, qualified and validated biomarker assays for ligand-binding
assays as well as the target acceptance criteria.
Assay
performance
characteristics
Screening
assays
Qualified
assays
Validated
assays
Target acceptance criteria Comments
Precision Yes Yes Yes In novel biomarker assays where
there is little or no clinical
information on the biomarker of
interest, targets for validation
performance for the between run
(inter-assay) and the within run
(intra-assay) CVs should be ≤25%
for the LLOQ QC and ≤20% for the
low, medium, high and ULOQ QCs
Inter-assay precision is the critical
assay performance characteristic to
obtain meaningful clinical results;
Acceptance criteria for sample
analysis can be set on a statistical
basis from the data produced at
validation, this then confirms the
assay is continually and
demonstrably under control
Accuracy: the
agreement
between the
observed value
and the expected
or nominal
(established)
value
Yes Yes Yes Range based on ±2 and 3 SD or
%RE
expected conc. blank
mean observed conc. 100=
+
)c m
6 @
When %RE is a multiple of the
inter-assay CV of the method;
Any QC results >±3 SD is an
automatic failure criteria
Accuracy is not always achievable
with biomarkers due to the
presence of binding proteins or
targets;
Different acceptance rules can be
applied to this information (e.g.,
±2 SD = warning, everything has to
be within ±3 SD, and the difference
between the lowest and highest
QC on a batch should not exceed
4 SD)
Parallelism Yes Yes Yes Back-calculated dilution adjusted
results (% recovery) within ±3 SD
(three-times inter-assay %CV)
At least three to ten samples from
normal or diseased individuals
(depending upon biomarker
concentration);
Since parallelism can demonstrate
matrix interference effects, other
tests can also be done;
Optional: 3–5 individuals with
hemolysis and 3–5 individuals with
lipidemia for validated assay
Specificity No Yes (optional) Yes The specificity will be evaluated by
spiking the matrix with the
potential reactive analyte at high,
medium and low QC levels;
For a qualified assay, specificity is
optional depending on the
biomarker of interest. For example,
NRP1 biomarker will need to be
checked on the cross-reactivity of
NRP2. Cross-reactivity provided by
vendor should be sufficient for
qualified assays
%RE: Percentage relative error; HQC: High QC; LQC: Low QC; MQC: Medium QC; PRA: Potential reactive analyte; TA: Target analyte.
Total % reactivity
average
TA
PRA
100 ;
TA
PRA
100 ;
TA
PRA
100
HQC
HQC
MQC
MQC
LQC
LQC
=
)
)
)
c
c
c
m
m
m
;
;
;
E
E
E
Recommendations on biomarker bioanalytical method validation | White Paper
www.future-science.com 2443future science group

6. without this, it is difficult to be certain what is
being measured. For LC–MS/MS methods, the
measurement of the mass of the ions provides a
degree of selectivity and theoretical transitions
can be chosen. The other parameter that should
be measured is the precision of measurement to
allow statistical evaluation of the significance of
any PD change in the biomarker.
Future perspective
The GCC will continue to provide recommenda-
tions on hot topics in bioanalysis of global inter-
est and expand its membership by coordinating
its activities with regional and international
meetings held by the pharmaceutical industry.
Please contact the GCC [102] for the dates and
times of future GCC closed forums, and for all
membership information.
Acknowledgements
The GCC would like to thank the following: R Houghton
and R Green (Quotient) for leading this initiative, design-
ing the survey, collating the results and making this article
a reality; D Gouty (Intertek Alta Immunochemistry),
J Allinson (Icon) and M Losauro (Intertek Alta
Immunochemistry) for critical review and edition of this
Table 2. Suggested requirements for screening, qualified and validated biomarker assays for ligand-binding
assays as well as the target acceptance criteria. (cont.).
Assay
performance
characteristics
Screening
assays
Qualified
assays
Validated
assays
Target acceptance criteria Comments
Specificity –
test article
Yes Yes Yes Test article should be spiked into
matrix – preferably an unspiked matrix
that contains a significant
concentration of biomarker or a
mid-level QC sample. A range of
spikes from 10 to 300% expected Cmax
is advised;
Acceptance ±three-times inter-assay
%CV
N/A
Linearity on
dilution (using
spiked samples)
Yes
– only if
parallelism
cannot be
completed
Optional Yes
– only if
parallelism
cannot be
completed
R2
> 0.95;
Dilutional linearity is expressed in
terms of the agreement (%RE)
between the observed results and a
nominal target value (nominal value
plus endogenous) at three-times
inter-assay %CV within the range of
quantitation
Endogenous level needs to be
taken in consideration in the
calculation
Selectivity No Optional Yes Acceptance criteria based on the
range of QCs (3 SD or %RE)
To be reported;
Background need to be subtracted
first. If an individual is high
compared with the pool serum,
then selectivity will not pass
Benchtop
stability
No Optional Yes Acceptance criteria is based on QCs
(3 SD at each level of the QC range or
%RE)
%RE
expected conc. blank
mean observed conc. 100=
+
)c m
6 @
Matrice pool should be identical
than the one used for
determination of the range in
precision and accuracy runs
Freeze–thaw
stability
No Optional,
recommended
Yes Acceptance criteria is based on QCs
(3 SD at each level of the QC range or
%RE)
%RE
expected conc. blank
mean observed conc. 100=
+
)c m
6 @
Matrice pool should be identical
than the one used for
determination of the range in
precision and accuracy runs
Long-term
stability
No Optional,
recommended
Yes Acceptance criteria is based on QCs
(3 SD at each level of the QC range or
%RE)
%RE
expected conc. blank
mean observed conc. 100=
+
)c m
6 @
Matrice pool should be identical
than the one used for
determination of the range in
precision and accuracy runs
%RE: Percentage relative error; PRA: Potential reactive analyte; QCH: QC high; QCL: QC low; QCM: QC medium; TA: Target analyte.
White Paper | Global CRO Council for Bioanalysis (GCC)
Bioanalysis (2012) 4(20)2444 future science group

7. document; R Houghton and J Allinson for facilitating and
leading the discussion on biomarkers during the 5th GCC
(Barcelona, Spain) and 6th GCC (San Antonio, TX,
USA) meetings, respectively; I Dumont and S Martinez
(Algorithme Pharma) and T Harter (Unilabs York
Bioanalytical Solutions, currently working at Covance
Laboratories) for writing the first draft of this White Paper;
the GCC member companies who answered the biomarker
survey and sent comments and suggestions to complete this
White Paper; W Garofolo (GCC) for organizing the logis-
tics of the meetings and coordinating the review of this
document.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a finan-
cial interest in or financial conflict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert t­estimony, grants or patents received or
pending, or royalties. No writing assistance was utilized in
the production of this manuscript.
Box 1. Suggested minimum requirements for a qualified method with the option of setting acceptance criteria
based on the performance of the assay during the qualification process.
Ligand-binding assays
„„ Calibration
„„ Precision†
„„ Selectivity
„„ Parallelism‡
„„ Limited storage stability‡,§
„„ Specificity (optional)
Clinical analyzer methods
„„ Calibration
„„ Precision and accuracy
„„ Linearity of dilution (parallelism‡
)
„„ Selectivity/specificity
„„ Limited storage stability‡
LC–MS/MS methods
„„ Calibration
„„ Precision and accuracy
„„ Selectivity/specificity
„„ Matrix effects/parallelism‡
„„ Limited storage stability‡
„„ Sensitivity
†
Accuracy not applicable. If there is endogenous level present, then percentage relative error (%RE) should include the endogenous (blank) level in the calculation:
%RE
nominal value blank QC
observed value 1 100=
+
- )c m; E
‡
Due to the requirement for samples containing significant concentrations of the biomarker of interest, it may not be possible to conduct these tests until incurred
samples are available (with appropriate consent).
§
Long-term stability and freeze–thaw stability are critical steps for biomarkers as most of the sample aliquot is used to test multiple biomarkers and very often goes
above seven freeze–thaw cycles. They are also typically run at the end of the studies, so a 2-year long-term stability is needed.
Author affiliations
Except for the first three, company names are in alphabetical
order:
1
Quotient Bioresearch, Fordham, UK
2
Intertek Alta Immunochemistry, San Diego, CA, USA
3
Icon Development Solutions, Manchester, UK
4
Advion Bioanalytical Labs, a Quintiles Company, Ithaca, NY,
USA
5
Agilux Laboratories, Worcester, MA, USA
6
Algorithme Pharma/Simbec Research, Laval, QC, Canada/
Merthyr Tydfil, UK
7
Atlanbio, St-Nazaire, France
8
Avogadro, Toulouse, France
9
Celerion, Fehraltorf, Switzerland
10
Charles River, Edinburgh, UK
11
EMD Millipore, St Charles, MO, USA
(currently working at Celerion, Lincoln, NE, USA)
12
GCC
13
Huntingdon Life Sciences, Huntingdon, UK
14
Intertek Alta LCMS, San Diego, CA, USA
15
MPI Research, Mattawan, MI, USA
16
PPD, Richmond, VA, USA
17
QPS Netherlands BV, Groningen, The Netherlands
18
QPS Netherlands BV, Groningen, The Netherlands
(currently working at Eurofins, Groningen, The Netherlands)
19
Tandem Labs, Salt Lake City, UT, USA
20
Tandem Labs, West Trenton, NJ, USA
21
Unilabs York Bioanalytical Solutions, York, UK
(currently working at Covance Laboratories, Harrogate, UK)
22
Worldwide Clinical Trials, Austin, TX, USA
Recommendations on biomarker bioanalytical method validation | White Paper
www.future-science.com 2445future science group

8. References
1 Premkumar​‌ N, Lowes​‌ S, Jersey​J et al.
Formation of a Global Contract Research
Organization Council for Bioanalysis.
Bioanalysis 2(11), 1797–1800 (2010).
2 Lowes​‌ S, Jersey​J, Shoup R et al.
Recommendations on: internal standard
criteria; stability; incurred sample reanalysis
and recent 483s by the Global CRO Council
for Bioanalysis. Bioanalysis 3 (12), 1323–1332
(2011).
3 Lowes​‌ S, Jersey​J, Shoup R et al. 4th Global
CRO Council for Bioanalysis: coadministered
drugs stability, EMA/US FDA Guidelines,
483s and Carryover. Bioanalysis 4(7),
763–768 (2012).
4 Breda N, Garofolo F, Cruz Caturla M et al.
The third Global CRO Council (GCC) for
Bioanalysis at the International Reid
Bioanalytical Forum. Bioanalysis 3(24),
2721–2727 (2011).
5 Boterman M, Doig M, Breda M et al.
Recommendations on ISR in multi‑analyte
assays, QA/bioanalytical consultants and
GCP by Global CRO Council for Bioanalysis
(GCC). Bioanalysis 4(14) 1723–1730 (2012).
6 Boterman M, Doig M, Breda M et al.
Recommendations on the interpretation of
the new European Medicines Agency
Guideline on Bioanalytical Method
Validation by Global CRO Council for
Bioanalysis (GCC). Bioanalysis 4(6), 651–660
(2012).
7 US Department of Health and Human
Services, FDA, Center for Drug Evaluation
and Research, Center for Veterinary
Medicine. Guidance for industry:
bioanalytical method validation. Rockville,
MD, USA (2001).
8 European Medicines Agency, Committee for
Medicinal Products for Human Use
(CHMP). Guideline on Bioanalytical Method
Validation. London, UK (2011).
9 Lee JW, Devanaryan V, Barrett Y C et al.
Fit-for-purpose method development and
validation for successful biomarker
measurement. Pharm. Res. 23(2), 312–328
(2006).
10 Wu Y, Lee J, Uy L et al. Tartrate-resistant acid
phosphatase (TRACP 5b): A biomarker of
bone resorption rate in support of drug
development: Modification, validation and
application of the BoneTRAP®
kit assay.
J. Pharm. Biomed. Anal. 49 (5), 1203–1212
(2009).
11 Chau CH, Rixe O, McLeod H, Figg WD.
Validation of analytical methods for
biomarkers employed in drug development.
Clin. Cancer Res. 14(19), 5967–5976 (2008).
12 Cummings J, Raynaud F, Jones L et al.
Fit-for-purpose biomarker method validation
for application in clinical trials of anticancer
drugs. Br. J. Cancer 103, 1313–1317 (2010).
13 Valentin M, Ma S, Zhao A et al. Validation of
immunoassay for protein biomarkers:
bioanalytical study plan implementation to
support pre-clinical and clinical studies.
J. Pharm. Biomed. Anal. 55 (5), 869–877
(2011).
14 US Department of Health and Human
Services, US FDA, Center for Drug
Evaluation and Research. Code of Federal
Regulations Title 21, Part 58: Good
Laboratory Practice For Nonclinical
Laboratory Studies. MD, USA (2009).
15 Nowatzke W, Cole TG, Bowsher RR.
Systematic analytical validation of commercial
kits for the determination of novel biomarkers
for clinical drug development. Bioanalysis
2(2), 237–247 (2010).
„„ Websites
101 Clinical and Laboratory Standards Institute
(CLSI) guidelines (formerly NCCLS) for
Biomarkers.
www.clsi.org
102 GCC.
www.global-cro-council.org
White Paper | Global CRO Council for Bioanalysis (GCC)
Bioanalysis (2012) 4(20)2446 future science group