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The 9th GCCClosed Forum was held just prior to the 2015 Workshop on Recent Issues in Bioanalysis (WRIB) in Miami, FL, USA on 13 April 2015. In attendance were 58 senior-level participants, from eight countries, representing 38 CRO companies offering bioanalytical services. The objective of this meeting was for CRO bioanalytical representatives to meet and discuss scientific and regulatory issues specific to bioanalysis. The issues selected at this year's closed forum include CAPA, biosimilars, preclinical method validation, endogenous biomarkers, whole blood stability, and ELNs. A summary of the industry's best practices and the conclusions from the discussion of these topics is included in this meeting report.

The 2014 8th Workshop on Recent Issues in Bioanalysis (8th WRIB), a 5-day full immersion in the evolving field of bioanalysis, took place in Universal City, California, USA. Close to 500 professionals from pharmaceutical and biopharmaceutical companies, contract research organizations and regulatory agencies worldwide convened to share, review, discuss and agree on approaches to address current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches and immunogenicity. From the prolific discussions held during the workshop, specific recommendations are presented in this 2014 White Paper. As with the previous years’ editions, this paper acts as a practical tool to help the bioanalytical community continue advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2014 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations for Hybrid LBA/LCMS, Electronic Laboratory Notebook and Regulatory Agencies’ Input. Part 1 (Small molecules bioanalysis using LCMS) was published in the Bioanalysis issue 6(22) and Part 3 (Large molecules bioanalysis using LBA and Immunogenicity) will be published in the Bioanalysis issue 6(24).

The 2014 8th Workshop on Recent Issues in Bioanalysis (8th WRIB), a 5-day full immersion in the evolving field of bioanalysis, took place in Universal City, California, USA. Close to 500 professionals from pharmaceutical and biopharmaceutical companies, contract research organizations and regulatory agencies worldwide convened to share, review, discuss and agree on approaches to address current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches and immunogenicity. From the prolific discussions held during the workshop, specific recommendations are presented in this 2014 White Paper. As with the previous years’ editions, this paper acts as a practical tool to help the bioanalytical community continue advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2014 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations for Large molecules bioanalysis using LBA and Immunogenicity. Part 1 (Small molecules bioanalysis using LCMS) and Part 2 (Hybrid LBA/LCMS, Electronic Laboratory Notebook and Regulatory Agencies' Input) were published in the Bioanalysis issues 6(22) and 6(23), respectively.

The 2014 8th Workshop on Recent Issues in Bioanalysis (8th WRIB), a 5-day full immersion in the evolving field of bioanalysis, took place in Universal City, California, USA. Close to 500 professionals from pharmaceutical and biopharmaceutical companies, contract research organizations and regulatory agencies worldwide convened to share, review, discuss and agree on approaches to address current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches and immunogenicity. From the prolific discussions held during the workshop, specific recommendations are presented in this 2014 White Paper. As with the previous years’ editions, this paper acts as a practical tool to help the bioanalytical community continue advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2014 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for small molecule bioanalysis using LCMS. Part 2 (Hybrid LBA/LCMS, Electronic Laboratory Notebook and Regulatory Agencies’ input) and Part 3 (Large molecules bioanalysis using LBA and Immunogenicity) will be published in the upcoming issues of Bioanalysis.

The 8th GCC Closed Forum for Bioanalysis was held in Baltimore, MD, USA on 5 December 2013, immediately following the 2013 AAPS Workshop (Crystal City V): Quantitative Bioanalytical Methods Validation and Implementation – The 2013 Revised FDA Guidance. This GCC meeting was organized to discuss the contents of the draft revised FDA Guidance on bioanalytical method validation that was published in September 2013 and consolidate the feedback of the GCC members. In attendance were 63 senior-level participants, from seven countries, representing 46 bioanalytical CRO companies/sites. This event represented a unique opportunity for CRO bioanalytical experts to share their opinions and concerns regarding the draft FDA Guidance, and to build unified comments to be provided to the FDA.

The 2013 7th Workshop on Recent Issues in Bioanalysis was held in Long Beach, California, USA, where close to 500 professionals from pharmaceutical and biopharmaceutical companies, CROs and regulatory agencies convened to discuss current topics of interest in bioanalysis. These ‘hot’ topics, which covered both small and large molecules, were the starting point for fruitful exchanges of knowledge, and sharing of ideas among speakers, panelists and attendees. The discussions led to specific recommendations pertinent to bioanalytical science. Such as the previous editions, this 2013 White Paper addresses important bioanalytical issues and provides practical answers to the topics presented, discussed and agreed upon by the global bioanalytical community attending the 7th Workshop on Recent Issues in Bioanalysis.

The 6th Global CRO Council for Bioanalysis (GCC) Closed Forum was held on 27 March 2012 in San Antonio, TX, USA, the day before the start of the 6th Workshop on Recent Issues in Bioanalysis. The attendance consisted of 45 bioanalytical CRO senior-level representatives on behalf of 37 CRO companies/sites from six countries. In addition to following up on the issue of co-administered drugs stability and on recommendations regarding the European Medicines Agency guideline, this GCC Closed Forum discussed topics of current interest in the bioanalytical field with focus on ligand-binding assays, such as lot changes for critical reagents, positive controls and reference standards, specificity for endogenous compounds, qualification and validation of biomarker assays, approach for biosimilars and criteria for LC–MS assays of small versus large molecules.

Over 400 professionals representing pharmaceutical companies, CROs, and multiple regulatory agencies participated in the 6th Workshop on Recent Issues in Bioanalysis (WRIB). Like the previous sessions, this event was in the format of a practical, focused, highly interactive and informative workshop aiming for high-quality, improved regulatory compliance and scientific excellence. Numerous ‘hot’ topics in bioanalysis of both small and large molecules were shared and discussed, leading to consensus and recommendations among panelists and attendees representing the bioanalytical community. The major outcome of this year’s workshop was the noticeable alignment of multiple bioanalytical guidance/guidelines from different regulatory agencies. This represents a concrete step forward in the global harmonization of bioanalytical activities. The present 2012 White Paper acts as a practical and useful reference document that provides key information and solutions on several topics and issues in the constantly evolving world of bioanalysis.

Senior representatives of GCC member companies have thoroughly evaluated and discussed the new European Medicines Agency (EMA; July 2011 [1]) Guideline on Bioanalytical Method Validation (BMV), during the 4th GCC (23 October 2011, Washington DC, USA) and 5th GCC (14 November 2011, Barcelona, Spain) Closed Forums. These North American and European events provided a unique opportunity for CRO leaders to openly share opinions and perspectives and to agree on unified bioanalytical recommendations specifically in relation with the new EMA guideline. The Global CRO Council for Bioanalysis (GCC) [101] is a global independent group of many Contract Research Organization (CRO) leaders. The GCC was formed in September 2010 to meet regularly and discuss bioanalytical issues and regulatory challenges, many of them unique to the outsourcing industry. The outcome of the discussions held as part of these GCC closed forum meetings are shared with the global bioanalytical community via pertinent publications [2–6] and appropriate conference presentations. Prior to the issue of this new guideline, the November 2009 Draft EMA Guideline on BMV defined the proposed guideline and criteria of the EMA on validation of bioanalytical methods and their application in the analysis of study samples from animal and human studies [7]. The EMA Guideline states that the validation of the bioanalytical methods to be used on non-clinical pharmacotoxicological studies to be submitted in a marketing authorization application should be performed following the Recommendations on the interpretation of the new European Medicines Agency Guideline on Bioanalytical Method Validation by Global CRO Council for Bioanalysis (GCC)

The prevalence of painful diabetic peripheral neuropathy (PDN) is about 20% in patients with type 2 diabetes and 5% in those with type 1. Patients should be systematically questioned concerning suggestive symptoms, as they are not usually volunteers. As PDN is due to small-fibre injury, the 10 g monofilament pressure test as well as the standard electrophysiological procedures may be normal. Diagnosis is based on clinical findings: type of pain (burning discomfort, electric shock-like sensation, aching coldness in the lower limbs); time of occurrence (mostly at rest and at night); and abnormal sensations (such as tingling or numbness). The DN4 questionnaire is an easy-to-use validated diagnostic tool. Three classes of drugs are of equal value in treating PDN: tricyclic antidepressants; anticonvulsants; and selective serotonin-reuptake inhibitors. These compounds may be prescribed as first-line therapy following pain assessment using a visual analogue scale. If the initial drug at its maximum tolerated dose does not lead to a decrease in pain of at least 30%, another drug class should be prescribed; if the pain is decreased by 30% but remains greater than 3/10, a drug from a different class may be given in association.

The 5th Workshop on Recent Issues in Bioanalysis (WRIB) was organized by the Calibration and Validation Group as a 2-day full immersion workshop for pharmaceutical companies, CROs and regulatory agencies to discuss, review, share perspectives, provide potential solutions and agree upon a consistent approach to recent issues in the bioanalysis of both small and large molecules. High quality, better compliance to regulations and scientific excellence are the foundation of this workshop. As in the previous editions of this significant event, recommendations were made and a consensus was reached among panelists and attendees, including industry leaders and regulatory experts representing the global bioanalytical community, on many ‘hot’ topics in bioanalysis. This 2011 White Paper is based on the conclusions from this workshop, and aims to provide a practical reference guide on those topics.

The 1st Conference in Asia-Pacific on Recent Issues in Bioanalysis was organized by the Calibration and Validation Group. This event, a 2-day full-immersion conference, was the first of this kind in the Asia-Pacific region, following four successful editions held in Montreal, Canada. This conference brought together scientists and experts from across Asia-Pacific and the rest of the world to discuss, review, share perspectives, provide potential solutions and agree upon consistent approaches on recent issues in bioanalysis. A total of 27 invited speakers from worldwide regulatory agencies, pharmaceutical companies and CROs provided interesting and pertinent oral presentations. All discussions were focused on high-quality, better compliance to regulations and scientific excellence.

The Global CRO Council for Bioanalysis (GCC), a global independent consortium bringing together many senior level CRO representatives, was created in 2010 in order to openly discuss and share opinions on scientific and regulatory issues specific to the bioanalytical field [1]. Since its formation, the GCC members have met on a regular basis to discuss various topics and challenges faced by bioanalytical CRO companies. Several conference reports of past GCC meetings were published to share the discussions held during these events [2–4]. In addition, the GCC also published several influential White Papers on topics of widespread interest in bioanalysis [5–9]. These White Papers provide unified GCC recommendations that are helpful to the global bioanalytical community. The 7th GCC Closed Forum for Bioanalysis took place in Long Beach, CA, USA on 8 April 2013, one day before the start of the 7th Workshop on Recent Issues in Bioanalysis (WRIB). In attendance were 46 senior-level participants from six countries, representing 37 bioanalytical CRO companies/sites. This event represented a good opportunity for bioanalytical experts from CROs to share and discuss these issues of concern for the outsourcing industry. The 7th GCC Closed Forum was chaired by Mario Rocci, who started the meeting by communicating the official admonition statement, as has been done in all previous editions [1]. Prior to initiating discussions, participants introduced themselves. As in previous GCC meetings, multiple topics of 7th GCC Insights: incurred samples use; fitfor-purpose validation, solution stability, electronic laboratory notebook and hyperlipidemic matrix testing

The topic of incurred sample stability (ISS) has generated considerable discussion within the bioanalytical community in recent years. The subject was an integral part of the seventh annual Workshop on Recent Issues in Bioanalysis (WRIB) held in Long Beach, CA, USA, in April 2013, and at the Global CRO Council for Bioanalysis (GCC) meeting preceding it. Discussion at both events focused on the use of incurred samples for ISS purposes in light of results from a recent GCC survey completed by member companies. This paper reports the consensus resulting from these discussions and serves as a useful reference for depicting ISS issues and concerns, summarizing the GCC survey results and providing helpful recommendations on ISS in the context of bioanalytical method development and application.

Laurence Mayrand-Provencher has obtained a Master of Science in Chemistry from Université de Montréal. With over 3 years of experience as a scientist in the bioanalysis industry, he is now a scientist in method development at Algorithme Pharma. His experiences have led him to conduct robust and effective method development of bioanalytical assays, specifically in the LC–MS/MS field. Many regulatory agencies include in their guidelines the need to investigate the effect of lipemic plasma on the reliability of the data as part of a bioanalytical assay validation. Lipids can cause matrix effect, specificity and recovery issues, which can potentially lead to inaccurate data if left unaccounted for. However, finding the appropriate matrix type to be used to perform a lipemic plasma test is a major challenge, as the differences between those commercially available are not well known. The work reported herein describes the differences in lipid content between normal plasma, synthetic lipemic plasma mixes, and two types of natural lipemic plasma. The results obtained show that natural plasma with high triglycerides content should be used to perform a scientifically meaningful lipemic plasma test.

An open letter written by the Global CRO Council for Bioanalysis (GCC) describing the GCC survey results on stability data from co-administered and co-formulated drugs was sent to multiple regulatory authorities on 14 December 2011. This letter and further discussions at different GCC meetings led to subsequent recommendations on this topic of widespread interest within the bioanalytical community over the past 2 years.

Background: Recently, incurred sample reanalysis (ISR) has become a requirement in bioanalysis. The general guidance recommends investigating ISR failure to evaluate the suitability of an analytical method. In the case of acceptable ISR evaluation, there were no precise recommendations for further testing when sporadic values were obtained. Results: The ISR evaluation performed during a bioequivalence study for the anticonvulsant drug oxcarbazepine showed acceptable ISR results, but one particular chromatographic anomaly led to a thorough investigation. The finding of these tests showed that an oxcarbazepine phase II metabolite occasionally co-eluted with the drug and impacted oxcarbazepine’s quantitation through in-source conversion. Conclusion: This paper demonstrates the necessity of rigorous interpretation of ISR results and close monitoring of all subject sample results.

Objective:Family therapy has developed several approaches to framing questions within family meetings, but few of these techniques have been adapted for palliative care. We focus on the application of questioning techniques from systemic family therapy to palliative care. More specifically, we describe and give examples of the model of asking questions developed by Karl Tomm (1988) through its application in Family Focused Grief Therapy (FFGT), a preventive intervention delivered to high-risk families during palliative care and bereavement.Methods:First, the type of questions used across the course of therapy is explored based on the interventive questioning model. Then, a case example is provided to demonstrate the use and adaptation of this model in a palliative care setting.Results:At the beginning of therapy, the most frequent questions were linear and circular, moving around the family to build up a picture of events from everyone's perspective. As for the frequency of reflexive and strategic questions, these increased as the therapy progressed, bringing the family to new perspectives. The case example fleshes out the importance of each type of question, all of which have a proper place in the course of therapy.Significance of results:These illustrations highlight the value of having a model of questioning styles to guide the clinician when exploring palliative care issues, such as care provision, coping and grief, intimacy, and discussing death. This framework could be useful in guiding supervisors, trainees, and clinicians seeking to build skills and optimize their interventions in a palliative care setting.

Since urea and uric acid clearance are affected by the effective intravascular volume, we measured the fractional urea and uric acid excretion in cirrhosis. High urea and uric acid clearances were observed in 30 and 55 percent, respectively, of 20 consecutive cirrhotic patients with normal renal function. In seven patients with a high fractional uric acid excretion, 5 mg of isosorbide dinitrate every four hours for 24 hours induced a significant increase in the serum uric acid level (from 3.7 +/- 0.8 mg/dl to 4.4 +/- 0.8 mg/dl; less than 0.001) with a concomitant decrease in the fractional uric acid excretion (from 14.0 +/- 3.2 percent to 8.8 +/- 3.1 percent; less than 0.02). During the same test, the blood urea level increased from 3.3 +/- 1.1 mmol/liter to 4.1 +/- 1.2 mmol/liter (p less than 0.005) with a decrease in fractional excretion from 51 +/- 4.5 percent to 39 +/- 5 percent (p less than 0.001). The oral intake of sulfinpyrazone in six of these patients induced a normal uricosuric response. In two cirrhotic patients with ascites, 40 mg of furosemide associated with a 24-hour severe water restriction was also shown to normalize the high fractional excretion of both urea and uric acid. In nine patients with ascites, we observed a significant increase in blood urea and uric acid concentration despite the absence of change in creatinine clearance once ascites was removed by diuretics. On the basis of these findings, we believe that the high fractional excretion of both urea and uric acid frequently observed in cirrhosis is related to an increase in the effective vascular volume.