The 5th Global CRO Council for Bioanalysis (GCC) meeting, held in Barcelona, Spain, in November 2011, provided a unique opportunity for CRO leaders to openly share opinions, perspectives and to agree on bioanalytical recommendations on incurred sample reproducibility in multi-analyte assays, regulation of quality assurance/bioanalytical consultants and regulatory requirements for GCP.

1. White Paper
The Global CRO Council for Bioanalysis
(GCC) was formed in an effort to bring
together many senior-level representatives of
CROs to openly discuss bioanalysis and the
regulatory challenges, many of them unique
to the outsourcing industry. CROs are unique
in that they work with many different phar-
maceutical companies and agencies, which
results in a distinctive and comprehensive per-
spective on scientific approaches in relation to
regulatory requirements. More information
on GCC unique structure can be found in
the publication titled ‘Formation of a Global
Contract Research Organization Council for
Bioanalysis’ [1] and its scientific activities have
been subsequently published in articles and
White Papers [2–6].
Introduction
The 5th GCC meeting was held on 13 November
2011 in Barcelona, Spain. In attendance were
29 senior-level representatives from 24 CROs on
behalf of nine countries, mainly from Europe.
The topics selected for discussion, suggested at
the 3rd GCC meeting held in Guildford, UK,
on 3–4 July 2011 were:
n Assay qualification and validation: attaining
clear definitions in relation to biomarker
assays;
n European Medicines Agency (EMA)
­Bioanalytical Method Validation guideline;
n Incurred sample reproducibility (ISR) in
multi-analyte assays: aim of reaching a con-
sensus on the method of sample selection and
the number of samples to be assessed;
n Regulation of quality assurance (QA)/bioana-
lytical consultants and provide a list of recom-
mendations for hiring a ‘qualified ­consultant’;
n Regulatory requirements for good clinical
practice (GCP).
EMA Bioanalytical Method Validation
guideline
Following its publication in July 2011, the new
EMA bioanalytical guideline [7] was to be the
main topic on the agenda.
Recommendations on ISR in multi‑analyte
assays, QA/bioanalytical consultants and GCP
by Global CRO Council for Bioanalysis (GCC)
The 5th Global CRO Council for Bioanalysis (GCC) meeting, held in Barcelona, Spain, in November 2011, provided a
unique opportunity for CRO leaders to openly share opinions, perspectives and to agree on bioanalytical recommendations
on incurred sample reproducibility in multi-analyte assays, regulation of quality assurance/bioanalytical consultants and
regulatory requirements for GCP.
Timothy Sangster1
, John Maltas2
, Petra Struwe3
, Jim Hillier4
, Mark Boterman5
, Mira Doig6
,
Massimo Breda7
, Fabio Garofolo8
, Maria Cruz Caturla9
, Philippe Couerbe10
, Christine Schiebl3
,
Colin Pattison1
, Lee Goodwin11
, Rudi Segers12
, Wei Garofolo*13
, Lois Folguera14
, Dieter
Zimmer15
, Thomas Zimmerman15
, Maria Pawula16
, Daniel Tang17
, Chris Cox18
, Chiara
Bigogno19
, Dick Schoutsen20
, Theo de Boer21
, Rachel Green22
, Richard Houghton22
, Romuald
Sable23
, Christoff Siethoff24
, Tammy Harter25
& Stuart Best26
Due to the equality principals of Global CRO Council (GCC), the authors are presented in alphabetical order of company name,
with the exception of the first author who was the chair of the meeting and the second to fourth authors who provided a major
contribution to topics discussed (presented in alphabetical order of company name).
*Author for correspondence: Global CRO Council (GCC), 15 Sunview Dr, Toronto, Ontario, L4H 1Y3, 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
Keywords: consultant n EMA n GCC n GCP
1723ISSN 1757-618010.4155/BIO.12.172 © 2012 Future Science Ltd Bioanalysis (2012) 4(14), 1723–1730
For reprint orders, please contact reprints@future-science.com

2. The guideline on Bioanalytical Method
Validation was thoroughly evaluated and dis-
cussed via an extensive survey and during both
the 4th and 5th GCC Closed Forums. CRO
leaders were able to openly share opinions and
perspectives and to agree on unified bioanalyti-
cal recommendations specifically in relation to
this new EMA guideline. The following topics
were discussed:
n Reference standards: certificates of analysis
and internal standards (IS) (section 4.1);
n Calibration curve and accuracy (sections 4.1.4
and 4.1.5);
n IS stability, processed sample stability and
matrix effect (sections 4.1.8 and 4.1.9);
n Analysis of study samples and incurred sam-
ples reanalysis (sections 5, 5.1, 5.2, 5.5 and 6);
n Ligand binding assays (LBA) (section 7).
The GCC recommendations are presented in
the White Paper, ‘Global CRO Council (GCC)
Recommendations on the Interpretation of the
new EMA Guideline on Bioanalytical Method
Validation’ [5].
Assay qualification & validation for
biomarker assays
Due to the magnitude of this topic, the GCC
recommendations on biomarker validation will
be presented in an independent White Paper [6].
„„ Recommendation #1: ISR, including
multi-analyte assays
In 2006, at the 3rd AAPS/US FDA
Bioanalytical Workshop (Crystal City III) [8],
it was decided that ISR was to be conducted
for both non-clinical and clinical studies. At
the AAPS Workshop on ISR held in February
2008, specific recommendations on ISR,
including aspects to be considered in imple-
menting a robust ISR program, were presented
and discussed [9]. Several ‘non-consensus’ top-
ics were highlighted, including multi-analyte
methods. Between 2008 and 2011, ISR has
been discussed at subsequent conferences and
forums (WRIB, EBF, GCC), but no consensus
has been reached with respect to multi-analyte
methods. The new EMA bioanalytical guide-
line addresses ISR but not in detail regarding
multi-analyte assays.
A survey was circulated to the GCC European
members posing questions on the approach to
ISR, with particular reference to multi-analyte
assays.
From the survey and subsequent discus-
sions, the majority of CROs consider that ISR
is conducted to demonstrate both the validity
of incurred sample analysis and the perform-
ance/robustness of the analytical method in the
laboratory. It was the general opinion that ISR
should be independent (i.e., kept separate from
study sample analysis) and that reanalyzing a few
samples within a batch alongside study samples
may also not be adequate to assess reproducibility
of the method. It was considered that perform-
ing ISR in separate batches would also make any
investigations of trends or failures less compli-
cated. Additionally, it was reiterated that ISR
should be performed as soon as practical after
the original analysis to limit any influence of
incurred sample stability.
From the survey results, ISR on tissue analy-
sis is not always performed. For tissue analysis,
qualified methods have been recommended
within the bioanalytical community and fol-
lowing discussions it was recommended that
ISR should only be performed when the tissue
analysis is a primary end point of the study and
is performed using a validated assay.
For ISR in general, three options were dis-
cussed to determine how many of the samples
analyzed were to be reanalyzed:
n For bioequivalence studies reanalyze 10% of
samples and for non-bioequivalence studies
reanalyze 5% of samples, regardless of size;
n For studies with up to 1000 samples, reanalyze
10% of samples and for studies with over 1000
samples reanalyze 5% of samples, but at least
100 samples;
n For studies up to 1000 samples reanalyze 10%
of samples and for studies with over 1000 sam-
ples reanalyze 10% of the first 1000 samples
and 5% of any remaining samples.
The third option matches the EMA guideline
and was the one preferred by attendees. It is also
agreed that a minimum number of ISR samples
should be specified even if it is not regulated by
the FDA or the EMA; for example, 20 samples.
It was agreed that typically two samples from
a subject would be selected for ISR, one around
the tmax
and one close to the elimination phase.
For toxicology studies it was discussed whether
to select more samples from fewer groups
(e.g., the highest and lowest concentration
dose groups only) or fewer samples from more
White Paper | Sangster, Maltas, Struwe et al.
Bioanalysis (2012) 4(14)1724 future science group

3. groups. The general opinion was that perform-
ing ISR on the highest and lowest concentration
dose groups may not be sufficient as there could
be differences, for example in metabolite profile,
gender and dose group. It was also agreed that
for composite profiles, sample selection should
mimic profiles with an equal number of samples
from the tmax
and the elimination phase.
Only samples with concentrations at least
three-times the LLOQ concentration should be
selected. Samples that had undergone dilution
should be included, and where possible the same
dilution factor should be used for both analyses.
The setting of criteria for the selection of late
elimination phase samples (e.g., number of half
lives from the tmax
) was discussed but the consen-
sus was to leave the selection of late elimination
phase samples as it is currently – samples should
be selected ‘by visual inspection’ rather than by
calculation.
The use of split samples, for example, two
aliquots originating from the same sample
stored in similar containers under similar con-
ditions, was discussed and it was agreed that
each split is considered equivalent and the use
of different splits for ISR should be treated the
same as per sample analysis. It was agreed that
if there is insufficient sample volume remain-
ing of the initial aliquot or it has reached the
limit of the established freeze–thaw cycles then
another sample split should be used for the ISR
investigation. Additionally, how to apply ISR
to dried blood spot assays was discussed and it
was agreed that equivalence between spots is
established during validation and, therefore, a
different spot could be used for ISR.
Almost all ISR results are calculated by com-
paring the difference between the original and
ISR concentrations with the mean of the two
concentrations (as per Crystal City recommen-
dation and EMA guideline), though occasion-
ally a CRO may be requested to calculate ISR
using different criteria.
Further discussions covered extreme outliers
(e.g., >50% bias from the original value) and
trends, and when an investigation and/or reanaly-
sis should be performed. In summary, for extreme
outliers it was agreed that if the ISR acceptance
criteria were met then extreme outliers were not
required to be investigated unless they formed a
trend, and for trends (a series of results that show
commonality, i.e., in terms of runs, populations,
subjects or animals, time-points, dilutions and so
on) an investigation should be performed even if
ISR acceptance criteria were met.
From the survey and subsequent discussions,
the majority of members have performed ISR
on multi-analyte assays. Currently ISR inves-
tigations are conducted for each analyte with
sample selection based on all analytes, apply-
ing the same rules used for selecting samples for
single analyte ISR. As each analyte may have a
different concentration–time profile, this may
result in an increase in the number of sam-
ples per subject. However, all samples selected
should be used for ISR for all analytes, with the
exception of samples where results are less than
­three-times the LLOQ concentration. If the ISR
analysis is performed using a sample diluted
applying a validated dilution but the original
value was obtained from an undiluted sample
for that analyte (or vice versa), as long as the
measured concentration is greater than three-
times the LLOQ, the result with a different
dilution regime to the original analysis should
be reported, rather than reanalyzing again with
the dilution factor applied during the original
analysis.
For multi-analyte assays, where one or more
analytes are not being assessed (e.g., a batch
has been rejected for one analyte and is being
reanalyzed for that analyte alone), as data
could be generated for all analytes, it was dis-
cussed whether or not the data from the previ-
ously accepted analytes could be used for ISR.
Although it was agreed to not routinely use these
additional data, it was recognized that this could
be useful, for example where sample volume is
limited and only one more reanalysis is possible.
It is recommended that if these additional data
are to be used then this should be stated a priori
in the study plan or in an amendment.
The GCC recommendation on ISR is shown
in Box 1.
„„ Recommendation #2: regulation of
QA/bioanalytical consultants & provide a list
of recommendations for hiring a ‘qualified
consultant’
Findings from a mock FDA inspection con-
ducted by an independent QA consultant were
presented at the 3rd GCC Closed Forum and the
validity of some of these findings was debated.
The overall consensus was that some of the
potential findings raised by the QA consultant
were out of date or even incorrect. Therefore,
it was decided that the hiring of QA/bioana-
lytical consultants should be discussed in more
depth, and a survey was circulated to the GCC
European members posing questions on the
GCC recommendations on ISR | White Paper
www.future-science.com 1725future science group

4. hiring of consultants – 16 completed surveys
were returned.
From the survey, members consider that a
consultant should have state-of-the-art knowl-
edge of bioanalytical activities, understand qual-
ity practices with focus on GLP and/or GCP
and bring in specific expertise that may not be
available or may not be in adequate abundance
in-house.
GCC members sometimes hire consultants
themselves but often a consultant has been hired
by a client to act on their behalf. Members gen-
erally accept a consultant representing a client
company without restriction, although some
members do have a formalized process and
request details, references and so on. Almost half
of members check the expertise of the consultant
on arrival at their site.
Although some feel that consultants mandated
by a client think they need to find something rel-
evant to justify their mission, from experience,
members have found that consultants hired by
clients are mostly fair and complementary. It is
general opinion that although there are some
consultants who do not appear to be up to date
with current practices and thinking or are not
relevantly qualified, there are consultants who
are able to manage the regulatory and technical
aspects of bioanalytical activities.
Consultants hired by the CRO often work as
an independent workforce whilst following the
CRO’s standard operating procedures (SOPs),
and depending on the length of the assignment
they may have their own training documenta-
tion (CV/expertise summary) and may be listed
on the organization chart. However, these con-
sultants do not sign regulatory documents and
few members have confidence that a consultant
could be hired to implement a new topic without
support from the organization.
The main objectives for CROs hiring con-
sultants are: as a teacher to fill in a technical or
regulatory knowledge gap (e.g., IT/computer
system validation); as an investigator to con-
duct mock inspections and gap analysis; as a
partner by assisting with excess internal work-
load (e.g., peaks in QA, implementation of new
hardware or software); or to help maintain
independence of the QA function. None of the
members who contributed had ever hired a con-
sultant to act as a Study Director or Principal
Investigator.
Although most members do not have a spe-
cific procedure in place, recommendation and
reputation is often the starting point for hir-
ing a consultant, although there was general
agreement that a member may not feel comfort-
able hiring a consultant who was recently or
Box 1. The GCC recommendation on incurred sample reproducibility.
„„ The GCC recommends that incurred sample reproducibility (ISR) should be performed in discrete batches separated from the study
sample analysis within a short time period decided a priori based on knowledge of the stability of the analytes and matrix involved. ISR
should be calculated by comparing the difference between the original and ISR results with the mean of the two results.
„„ ISR is not required to be performed for tissue analysis unless the tissue analysis is a primary end point of the study and is performed
using a validated assay.
„„ For studies where up to 1000 samples are analyzed, reanalyze 10% of samples; for studies where more than 1000 samples are
analyzed, reanalyze 10% of the first 1000 samples with an additional 5% of samples above 1000 samples. At least 20 samples should
be analyzed. Typically two samples from a subject should be selected for ISR, one around the tmax
and one close to the elimination
phase, selected by visual inspection, and with concentrations at least three-times the LLOQ concentration.
„„ For toxicology studies, it is recommended that ISR should be performed in all dose groups covering both male and females and for
composite profiles sample selection should mimic profiles with an equal number of samples from the tmax
and elimination phase.
„„ For samples that had undergone dilution, the same dilution factor should be used for both analyses where possible. Additionally,
different sample splits/aliquots or dried matrix spots can be used for ISR analysis.
„„ For extreme outliers (>50%) the GCC recommends that if the ISR acceptance criteria are met then extreme outliers are not required
to be investigated unless they form a trend, and for trends an investigation should be performed even if ISR acceptance criteria are met.
„„ For multi-analyte assays, ISR should be conducted for each analyte and sample selection should be based on all analytes, applying the
same rules used for selecting samples for single analyte ISR. This may result in an increase in the number of samples per subject with
all samples selected to be used for ISR for all analytes, with the exception of samples where results are less than three-times the LLOQ
concentration. If the ISR analysis is performed using a sample diluted applying a validated dilution but the original value was obtained
from an undiluted sample for that analyte (or vice versa), as long as the measured concentration is greater than three-times the LLOQ,
the result with different dilution regimen to the original analysis should be reported.
„„ For multi-analyte assays, where a sample is being reanalyzed for a limited number of analytes, the additional data for the other
analyte(s) should not normally be used for ISR. If these data are, for example, in cases where sample volume is limited and only one
more reanalysis is possible then this should be stated a priori in the study plan or in an amendment.
White Paper | Sangster, Maltas, Struwe et al.
Bioanalysis (2012) 4(14)1726 future science group

5. currently working for a competitor. The cur-
rent process of hiring a consultant is mainly via
interviews in combination with a file review,
including assessment of CV and expertise. In
general, it is a QA representative or the test
facility management that approves that the
­consultant is qualified.
The GCC recommendation on consultants is
shown in Box 2.
„„ Recommendation #3: regulatory
requirements for GCP (contracts, study
conduct & training)
At the 3rd GCC Closed Forum, the imple-
mentation of GCP was discussed and it was
determined that knowledge and experience of
GCP varied widely across European countries.
With the aim of ensuring all members had the
knowledge to be able to implement GCP, it was
suggested that sharing of experiences between
members would facilitate this. A survey was cir-
culated to the GCC European members posing
questions on GCP experiences to date.
GCP is a collection of ethical and scientific
quality systems for designing, conducting and
reporting of clinical trials that involve partici-
pation of human subjects. GCP is required to
ensure the rights, safety and well-being of trial
subjects are protected and to ensure the credibil-
ity of the clinical trial data. GCP has developed
into formal guidelines as a result of instances
of abuse of human rights, harm to subjects and
serious fraud.
The European Clinical Trials Directive
2001/20/EC (EU CTD) was introduced to
establish standardization of research activity in
clinical trials throughout the European com-
munity [101]. It provides a framework that sets
out how clinical trials investigating the safety
or efficacy of a medicinal product in humans
must be conducted, including medicinal trials
with healthy volunteers and small-scale or pilot
studies. The aims of the EU CTD are to pro-
vide greater protection to subjects participating
in clinical trials, ensure quality of conduct and
harmonize regulation and conduct of ­clinical
trials throughout Europe.
The International Conference on
Harmonisation Guidance on Good Clinical
Practice (CPMP/ICH/135/95) is an inter-
national standard for GCP [102]. The Good
Clinical Practice Directive 2005/28/EC sup-
plements the EU CTD, strengthening the legal
basis for requiring Member States to comply
with the principles and guidelines of GCP, as set
out in the ICH-GCP guidelines [101]. However,
these guidelines offer no direct guidance on
how laboratory analysis should be conducted.
Therefore, the UK GLP monitoring author-
ity, the Medicines and Healthcare Products
Regulatory Agency (MHRA), produced a guid-
ance on the maintenance of regulatory compli-
ance in laboratories that perform the analysis or
evaluation of clinical trial samples [10]. The EMA
has now issued a reflection paper for laboratories
that perform the analysis or evaluation of clinical
trial samples [11].
For laboratories undertaking clinical sample
analysis, the accepted standards for GCP are
similar to those of GLP with respect to:
Box 2. The GCC recommendation on consultants.
„„ The GCC recommends that an organization has defined procedures for hiring consultants, including the initial selection, assessment of
qualifications and experience, approval process, integration within the organization and contractual arrangements, and for acceptance
of consultants acting on behalf of clients.
„„ The process for hiring consultants should be similar to hiring a new employee. The review of CVs should lead to a selection of
candidate(s) for interview, where the contents of the CV should be interrogated further, including qualifications, experience, testimonials
and continued relevant training (e.g., supplier’s training for hardware/software, attendance at regulatory and scientific meetings).
References should also be requested and followed up. A consultant should be fit-for-purpose, that is, they should be GLP, good clinical
practice as required, knowledgeable (up to date with technology/regulations) and have relevant consultancy experience.
„„ The process for accepting consultants acting on behalf of clients should be agreed between the CRO and client. The GCC recommends
that the client conducts the more detailed process for hiring consultants, whilst the CRO performs an additional brief CV review prior to
the visit and a brief interview on arrival.
„„ The GCC also suggests that CROs could, and often do, act as consultant for their clients; for example, CRO quality assurance
departments could perform facility audits for clients, as they have breadth and depth of knowledge and experience due to the
wide variety of clients that they support. CROs are also experts in their particular field, as their focus is bioanalysis rather than drug
development as a whole and, as such, are up to date with technology and regulatory requirements.
„„ The consensus of the GCC members was that working with qualified consultants could be an opportunity to decrease internal costs by
managing workflows and increasing knowledge and skills more efficiently. However, if consultants are to be more widely used, it may be
advisable for them to become regulated or affiliated to a set code or standard to ensure a consistent, high standard for all consultants.
GCC recommendations on ISR | White Paper
www.future-science.com 1727future science group

6. n Method validation, ISR;
n Repeat analysis;
n Data recording, reporting and retention of
data;
n Facilities and equipment maintenance;
n Computerized systems;
n QA and QC, SOPs and policies.
However, there are some important differ-
ences between GCP and GLP:
n In GCP, the sponsor or sponsor representative
is the Management Authority, that is, at the
bioanalytical CRO there is no equivalent role
to the GLP Study Director. Therefore, unlike
GLP, the sponsor has legal responsibilities
regarding integrity of data and conduct of the
study. The responsible scientist for bioanalysis
reports directly to the sponsor and must inform
the sponsor without delay of any serious breach,
which could affect either patient safety or the
scientific value/integrity of the trial. Examples
of such breaches include unscheduled breaking
of the blinding code, thus risking patient con-
fidentiality, unexpected test results or
­deviations from the clinical protocol;
n In GCP, the Principal Investigator is a health-
care professional and not the responsible
­bioanalytical scientist.
Box 3. The GCC recommendation on good clinical practice.
„„ The GCC recommends consideration of the following points concerning contracts:
„„ There should be a contract in place agreeing good clinical practice (GCP) compliance that identifies the responsibilities of all parties,
that is, sponsor, CRO, clinic and so on;
„„ A signed copy of the Clinical Trial Protocol (CTP) should be made available to the analytical laboratory;
„„ Other trial associated documentation should be available, for example laboratory manuals, written assurance that informed consent
has been obtained and so on;
„„ Relevant CTP amendments should be provided in a timely manner to the analytical laboratory via a mechanism agreed between the
sponsor and the analytical laboratory;
„„ The CTP should only include work covered by the informed consent given by the trial subjects;
„„ Consent change or withdrawal should be agreed to be communicated from the sponsor and the procedure identified in the CTP;
„„ The CTP should be understood – specifically aspects relating to the analysis to be performed at the analytical laboratory;
„„ An Analytical Phase Plan/Protocol (APP) describing the analytical work to be done, including a designated responsible scientist who
will manage the analytical phase and claim GCP compliance, should be agreed and signed by the sponsor;
„„ Additional work and subcontracting should have sponsor approval, be included in the CTP or CTP amendment and be covered by
informed consent;
„„ There should be no contradictions between any parts of the contract, for example, master service agreement, preferred provider
agreement, quote, CTP, APP and so on.
„„ The GCC recommends consideration of the following additional points concerning study conduct at the CRO:
„„ Management, quality assurance and analyst activity expectations similar to GLP;
„„ No confidential information should be evidenced or inferred by the sample label or accompanying documentation; a procedure should
be described at the analytical laboratory on how to deal with breaches of this nature;
„„ Policies for dealing with missing, unexpected or poorly labeled samples should be documented;
„„ Samples should not be analyzed until their identity is confirmed and approved by the sponsor;
„„ Potential serious breaches should be immediately reported to the sponsor so that the potential health and safety risks can be assessed;
„„ (Un)blinding should be covered by a sponsor agreed procedure, that is, included in the CTP, APP or a standard operating procedure
(e.g., Quarantine and notification to sponsor).
„„ The GCC recommends consideration of the following additional points concerning training at the CRO:
„„ All staff involved in the analysis or evaluation of clinical trial samples should receive GCP training commensurate with their roles and
responsibilities;
„„ It is appropriate for laboratory staff to receive periodic refresher training reflecting current statutory regulations and associated
guidance interpretation;
„„ Job descriptions should refer to roles and responsibilities for GCP activities;
„„ Competency statements should refer to GCP activities;
„„ Training records should be periodically reviewed, signed and dated to ensure that the information contained is current and remains
relevant.
„„ Although CROs are currently following regulatory guidelines, for example the European Medicines Agency, US FDA [12], Medicines and
Healthcare Products Regulatory Agency and so on, we would like to move towards using the term ‘regulated bioanalysis’ and move away
from using the terms GLP and GCP.
White Paper | Sangster, Maltas, Struwe et al.
Bioanalysis (2012) 4(14)1728 future science group

7. From the survey, a variety of regulatory guide-
lines are followed and quoted, including MHRA,
EMA, OECD, GLP, GCP, ISO17025, ICH and
Declaration of Helsinki. Most members have
some form of procedure for GCP in place, many
encompassing training, job descriptions, indi-
viduals’ roles and competency requirements with
respect to GCP, and requests for additional work.
Approximately half of the members have specific
SOPs for GCP in place, with some incorporating
GCP into their ­current SOPs.
The majority of members have only a bio-
analytical function, and few have the ability to
run a preclinical and/or clinical trial. Therefore,
only a small minority of members accept all of
the sponsors trial-related duties, including ini-
tiation and administration of the Clinical Trial
Protocol. However, it was widely acknowl-
edged that the quality of clinical protocols have
­noticeably improved following GCP inspections.
Approximately two-thirds of members had
already undergone an inspection for GCP, and
most would like certification for GCP, similar
to GLP certification. Those that also had clients
audits generally found no significant differences
from regulatory inspections (FDA, MHRA and
so on). The primary focus of GCP inspections
in practice has been concerned with contract
composition, training records, documentation
and data integrity, audit trails, traceability of
sample data, sample chain of custody, patient
confidentiality, patient safety, patient consent,
patient blinding and anonymity and reporting of
adverse reactions and potential breaches.
During the discussions one member presented
a finding from a GCP inspection where it was
claimed that the method was not well defined
(i.e., inappropriate range, as more than 3% of
samples were reassayed diluted). In this situa-
tion it was felt that the inspector evaluated under
their own personal approach as there are no
parameters or acceptance criteria described for
the number of diluted samples in any bioanalyti-
cal guidelines or official paper. No other attendee
had encountered this during an inspection and it
was considered that this was an ­isolated incident.
The GCC recommendation on GCP is shown
in Box 3.
Future perspective
The GCC will continue to provide recommen-
dations on hot topics in bioanalysis of global
interest and expand its membership by coordi-
nating its activities with the regional and inter-
national meetings held by the pharmaceutical
industry. Please contact the GCC for the dates
and times of future GCC Closed Meetings, and
for all membership information [103].
Acknowledgements
The GCC would like to thank T Sangster (Charles River)
for chairing the whole GCC 5th Closed Forum in
Barcelona; T Sangster (Charles River) and J Maltas
(BASi) for leading the discussion on ISR; P Struwe
(Celerion) for leading the discussion on Consultants; and,
J Hillier (Gen-Probe Life Sciences) for leading the discus-
sion on GCP; all the GCC member companies that have
answered the Surveys; T Harter (Unilabs York
Bioanalytical Solutions, presently at Covance
Laboratories) for writing the first draft of this White
Paper and for reviewing the document and incorporating
comments and suggestions; all the member representatives
that have 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.
Author affiliations
Company names in alphabetical order:
1
Charles River, Edinburgh, UK
2
BASi, Kenilworth, Warwickshire, UK
3
Celerion, Fehraltorf, Switzerland
4
Gen-Probe Life Sciences, Manchester, UK
5
ABL, Assen, The Netherlands
6
ABS Laboratories, Welwyn Garden City, UK
7
Accelera, Nerviano, Italy
8
Algorithme Pharma/Simbec Research, Laval, QC, Canada/
Merthyr Tydfil, UK
9
Anapharm Europe, Barcelona, Spain
10
ATLANBIO, Saint-Nazaire, France
11
Covance Laboratories, Harrogate, UK
12
Eurofins, Breda, The Netherlands
13
Global CRO Council
14
Harlan Laboratories, Breda, The Netherlands
15
Harlan Laboratories, Itingen, Switzerland
16
Huntingdon Life Sciences, Huntingdon, UK
17
ICON, Shanghai, China
18
Millipore BioPharma Services, Abingdon, UK
19
NiKem Research, Baranzate, Italy
20
NOTOX, ‘s-Hertogenbosch, The Netherlands
21
QPS Netherlands BV, Groningen, The Netherlands
22
Quotient Bioresearch, Fordham, UK
23
SGS, Wavre, Belgium
24
Swiss BioQuant AG, Reinach, Switzerland
25
Unilabs York Bioanalytical Solutions, York, UK;
presently at Covance Laboratories, North Yorkshire, UK
26
Xceleron, York, UK
GCC recommendations on ISR | White Paper
www.future-science.com 1729future science group

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White Paper | Sangster, Maltas, Struwe et al.
Bioanalysis (2012) 4(14)1730 future science group