Recommendations on ISR in multi‐analyte assays, QA/bioanalytical consultants and GCP by Global CRO Council for Bioanalysis (GCC)

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].

IntroductionThe 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:nAssay qualification and validation: attaining

clear definitions in relation to biomarker assays;

nEuropean Medicines Agency (EMA) Bioanalytical Method Validation guideline;

nIncurred 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;

nRegulation of quality assurance (QA)/bioana-lytical consultants and provide a list of recom-mendations for hiring a ‘qualified consultant’;

nRegulatory 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: [email protected]; 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

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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:

nReference standards: certificates of analysis and internal standards (IS) (section 4.1);

nCalibration curve and accuracy (sections 4.1.4 and 4.1.5);

nIS stability, processed sample stability and matrix effect (sections 4.1.8 and 4.1.9);

nAnalysis of study samples and incurred sam-ples reanalysis (sections 5, 5.1, 5.2, 5.5 and 6);

nLigand 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 assaysDue to the magnitude of this topic, the GCC recommendations on biomarker validation will be presented in an independent White Paper [6].

n Recommendation #1: ISR, including multi‑analyte assaysIn 2006, at the 3rd A APS/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, specif ic 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:nFor bioequivalence studies reanalyze 10% of

samples and for non-bioequivalence studies reanalyze 5% of samples, regardless of size;

nFor 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;

nFor 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 t

max 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

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Bioanalysis (2012) 4(14)1724 future science group

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 t

max 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 t

max) 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.

n 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

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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.n 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.

n 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.

n 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 t

max and one close to the elimination

phase, selected by visual inspection, and with concentrations at least three-times the LLOQ concentration.

n 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 t

max and elimination phase.

n 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.

n 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.

n 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.

n 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.



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.

n 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 Internat iona l 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.n 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.

n 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.

n 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.

n 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.

n 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.



nMethod validation, ISR;

nRepeat analysis;

nData recording, reporting and retention of data;

nFacilities and equipment maintenance;

nComputerized systems;

nQA and QC, SOPs and policies.

However, there are some important differ-ences between GCP and GLP:nIn 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-f identiality, unexpected test results or deviations from the clinical protocol;

nIn GCP, the Principal Investigator is a health-care professional and not the responsible bioanalytical scientist.

Box 3. The GCC recommendation on good clinical practice.n The GCC recommends consideration of the following points concerning contracts:

n 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;

n A signed copy of the Clinical Trial Protocol (CTP) should be made available to the analytical laboratory;n Other trial associated documentation should be available, for example laboratory manuals, written assurance that informed consent has been obtained and so on;

n 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;

n The CTP should only include work covered by the informed consent given by the trial subjects;n Consent change or withdrawal should be agreed to be communicated from the sponsor and the procedure identified in the CTP;n The CTP should be understood – specifically aspects relating to the analysis to be performed at the analytical laboratory;n 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;

n Additional work and subcontracting should have sponsor approval, be included in the CTP or CTP amendment and be covered by informed consent;

n 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.

n The GCC recommends consideration of the following additional points concerning study conduct at the CRO:n Management, quality assurance and analyst activity expectations similar to GLP;n 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;

n Policies for dealing with missing, unexpected or poorly labeled samples should be documented;n Samples should not be analyzed until their identity is confirmed and approved by the sponsor;n Potential serious breaches should be immediately reported to the sponsor so that the potential health and safety risks can be assessed;n (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).

n The GCC recommends consideration of the following additional points concerning training at the CRO:n All staff involved in the analysis or evaluation of clinical trial samples should receive GCP training commensurate with their roles and responsibilities;

n It is appropriate for laboratory staff to receive periodic refresher training reflecting current statutory regulations and associated guidance interpretation;

n Job descriptions should refer to roles and responsibilities for GCP activities;n Competency statements should refer to GCP activities;n Training records should be periodically reviewed, signed and dated to ensure that the information contained is current and remains relevant.

n 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.



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 perspectiveThe 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].

AcknowledgementsThe 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 disclosureThe 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 t estimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Author affiliationsCompany names in alphabetical order:1Charles River, Edinburgh, UK2BASi, Kenilworth, Warwickshire, UK3Celerion, Fehraltorf, Switzerland4Gen-Probe Life Sciences, Manchester, UK5ABL, Assen, The Netherlands6ABS Laboratories, Welwyn Garden City, UK7Accelera, Nerviano, Italy8Algorithme Pharma/Simbec Research, Laval, QC, Canada/Merthyr Tydfil, UK 9Anapharm Europe, Barcelona, Spain10ATLANBIO, Saint-Nazaire, France11Covance Laboratories, Harrogate, UK12Eurofins, Breda, The Netherlands13Global CRO Council14Harlan Laboratories, Breda, The Netherlands15Harlan Laboratories, Itingen, Switzerland16Huntingdon Life Sciences, Huntingdon, UK17ICON, Shanghai, China18Millipore BioPharma Services, Abingdon, UK19NiKem Research, Baranzate, Italy20NOTOX, ‘s-Hertogenbosch, The Netherlands21QPS Netherlands BV, Groningen, The Netherlands22Quotient Bioresearch, Fordham, UK23SGS, Wavre, Belgium24Swiss BioQuant AG, Reinach, Switzerland25Unilabs York Bioanalytical Solutions, York, UK; presently at Covance Laboratories, North Yorkshire, UK 26Xceleron, York, UK



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Recommendations on ISR in multi‐analyte assays, QA/bioanalytical consultants and GCP by Global CRO Council for Bioanalysis (GCC)