On May 10, 2024, the Global CRO Council for Bioanalysis (GCC) successfully held the 17th Closed Forum in San Antonio, USA. This forum brought together representatives from international bioanalytical contract research organizations (CROs) to discuss scientific and regulatory issues in the field of bioanalysis. The meeting covered eleven major topics, including integrative bioanalysis, patient-centric sampling, emerging technologies, data integrity, discrepancies in ELISpot data, cross-validation harmonization, ultrasensitive immunogenicity analysis platforms, remote regulatory assessments, shedding assays by PCR, and tissue biomarker analysis.
This article will summarize the core content of the meeting, providing references for bioanalysts, pharmaceutical companies, and regulatory agencies.
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Background
The GCC was established in 2010 as an independent global alliance aimed at bringing together CRO leaders to discuss scientific and regulatory issues related to bioanalysis. Since its inception, the GCC has regularly held meetings and published reports to share discussion results and industry opinions. Additionally, the GCC has released several white papers offering unified recommendations on hot topics in bioanalysis, gaining recognition in the global bioanalysis community.
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Topic 1: Integrative Bioanalysis
This session discussed the best strategies for managing multiple platforms (such as triple quadrupole, high-resolution mass spectrometry, hybrid analysis, ligand binding analysis, etc.) within the same laboratory to address complex bioanalytical challenges.
Platform Comparison and Selection
• LBA vs LC-MS: Ligand binding analysis (LBA) is generally less expensive and suitable for large clinical studies, while hybrid analysis (IA-MS) combines antibody enrichment with LC-MS/MS selectivity, making it more suitable for preclinical studies or situations with limited reagents.
• Advantages of Hybrid Analysis: It can be used for large molecules, biotherapeutics, or biomarker studies, with capabilities for multi-species conversion, distinguishing endogenous substances, and adapting to non-ideal standards.
• Direct Enzymatic Digestion vs Hybrid Analysis vs LBA: The selection strategy should consider method development budget, availability of key reagents, and the purpose of the assay.
Analysis of Oligonucleotides and Antibody-Drug Conjugates (ADCs)
• Analysis of oligonucleotides (such as antisense oligonucleotides, siRNA, aptamers) can be performed using hybrid or chromatographic platforms, with platform selection based on scientific objectives, sensitivity, and selectivity.
• ADC analysis strategies depend on conjugation chemistry, required information, and reagent availability. The drug-to-antibody ratio (DAR) is a key factor in pharmacokinetics (PK) considerations.
Laboratory Operations and Regulatory Interaction
• Sample dilution, stability, team collaboration, and training need systematic management.
• Currently, there is a lack of formal guidelines for hybrid analysis, and it is recommended to flexibly accept a 20/25% standard in PK and biomarker analysis, clarifying residual carryover and sample arrangement strategies.
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Topic 2: Patient-Centric Sampling (PCS)
PCS refers to the collection of biological samples (such as blood, saliva) by patients or caregivers in non-clinical settings. Although PCS offers advantages in clinical convenience and remote trials, its application also presents a series of bioanalytical challenges.
Key Considerations
• Sample Suitability: The feasibility of PCS must be assessed based on the characteristics of the analyte, sample volume, and storage conditions. For example, immunogenicity analysis is currently not suitable for PCS.
• Compliance and Training: Patient compliance, device usability, sample contamination, and coagulation issues are major challenges.
• Validation Requirements: If samples are used for critical treatment decisions, FDA approval is required, along with dual validation of scientific analysis and device technology.
Recommended Suggestions
• Develop CRO-friendly decision trees and engage central laboratories/CROs for professional advice early on.
• Explore the role of GCC in standardizing training, equipment evaluation, and cross-study coordination.
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Topic 3: Implementation of Emerging Technologies in CROs
Next-Generation Sequencing (NGS)
NGS is widely used in genomic analysis, but its implementation in CROs still faces challenges such as system selection, validation, and data interpretation. The meeting called for the GCC to develop specific recommendations to clarify analytical methods, sensitivity requirements, and cross-platform comparability.
Artificial Intelligence (AI) and Machine Learning (ML)
AI has potential in method development, data analysis, and quality control, but it also brings regulatory and validation challenges:
• The role of AI in decision-making needs to be clearly defined, maintaining scientific oversight and documentation.
• AI validation strategies should be developed, with attention to data security and privacy regulations.
Olink® Multiplex Protein Detection and Spectral Flow Cytometry
• Olink achieves high-throughput, high-sensitivity protein screening through proximity extension technology (PEA), suitable for biomarker discovery.
• Spectral flow cytometry (SFC) provides high-dimensional data analysis capabilities, but panel design and validation complexity require further standardization.
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Topic 4: Data Integrity Guidelines (FDA Draft)
In April 2024, the FDA released a draft guideline on “Data Integrity in In Vivo Bioavailability and Bioequivalence Studies,” emphasizing the sponsor’s ultimate responsibility for data quality and proposing the following recommendations:
• Establish a quality management system covering data governance, record management, training, and audit trails.
• Enhance communication and documentation between sponsors and testing sites.
• It is recommended that GCC members develop unified interpretations and recommended practices after the guideline is finalized.
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Topic 5: Sample Reconciliation and Data Coordination
Sample metadata reconciliation is a key step in ensuring data quality, but there are currently issues such as complex data transfer, inconsistent audit trails, and cumbersome processes. The meeting suggested:
• Develop a white paper through GCC surveys to clarify minimum data transfer standards and templates.
• Promote practice coordination among CROs to enhance data exchange efficiency and consistency.
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Topic 6: Discrepancies in ELISpot Data and Standardization
ELISpot assays have unique value in cellular immune monitoring, but their results are influenced by various variables:
• Quality of PBMCs: Transport conditions, cryopreservation effectiveness, and cell counts all affect results.
• Operations and Protocols: Lack of standardized protocols leads to inter-laboratory differences.
• Data Analysis: Low spot counts lead to high coefficients of variation, requiring cautious interpretation.
Recommended Measures
• Standardize sample collection, processing, and analysis workflows.
• Use cell reference samples to optimize experiments and inter-laboratory comparisons.
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Topic 7: Cross-validation Coordination Needs
PK and Immunogenicity Analysis
• ICH M10 provides advanced recommendations for cross-validation, but terminology and execution details still need clarification.
• ADA analysis lacks formal guidelines; it is recommended to choose classification data or minimum significant ratio (MSR) assessments based on usage.
Statistics and Inter-platform Validation
• Regression analysis, Bland-Altman plots, and other methods can be used for data comparison.
• It is recommended to maintain flexibility in cross-validation plans, driven by scientific rationality.
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Topic 8: Ultrasensitive Immunogenicity Analysis Platforms
Ultrasensitive platforms (such as ImmunoPCR, Simoa) can enhance detection sensitivity and drug tolerance, but their application in immunogenicity analysis is still exploratory. The meeting found through surveys that:
• Platforms are mostly used for biomarker discovery, with few used for PK/ADA.
• The main driving factors are sponsor needs and analyte characteristics.
• Challenges include reagent costs, validation complexity, and lack of case studies.
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Topic 9: Remote Regulatory Assessments (RRA)
The FDA widely adopted RRA for remote oversight inspections during the pandemic, with success relying on:
• Close collaboration and communication plans between CROs and sponsors.
• Preparation of materials in advance, clear role definitions, and use of video conferencing and daily briefings.
• Emphasizing the importance of audit trails and document management.
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Topic 10: Shedding Assays by qPCR/dPCR
Data Reporting and Interpretation
• Reporting units need to be standardized (e.g., copies per volume or /μg DNA).
• Low DNA yield samples can be directly loaded without dilution to improve detection rates.
• Three consecutive negative time points may be considered for stopping analysis, but careful validation is required.
Regulatory Compliance
• Shedding analysis should be qualitative or validated based on usage, development stage, and risk assessment.
• Currently, ISR (incurred sample reanalysis) is not recommended, and long-term stability should consider extraction variability.
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Topic 11: Progress on Tissue Biomarker Analysis White Paper
Biomarker analysis technologies are rapidly evolving, but regulatory guidelines lag behind. The GCC will release a white paper on the validation of tissue biomarker analysis in 2025, clarifying:
• The scope includes molecular biomarkers in tissues such as epithelium, muscle, nerve, and bone, excluding liquid samples and physiological markers.
• A call for future guidelines that better adapt to new technologies and complex molecules.
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Summary and Outlook
This GCC Closed Forum deeply explored multiple cutting-edge and challenging topics in the field of bioanalysis, resulting in a wealth of consensus and recommendations. The GCC will continue to serve as an important platform for the global bioanalysis community, promoting industry standardization and regulatory coordination.
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Original Source: Zimmer, J., Odell, M., Johnson, D., et al. (2025). 17th GCC Closed Forum: Integrative Bioanalysis, Patient-centric Sampling, Emerging Technologies, Data Integrity, Sample Reconciliation, Discrepancies of ELISpot Data, Cross-validation Harmonization, Ultrasensitive Platforms for ADA Assays, Remote Regulatory Assessments, Shedding Assays by PCR, and Biomarker Tissue Assays. Bioanalysis, 17(12), 769–786.
Note: This article is a translation of an academic literature review assisted by ChatGPT-4o, aimed at popularizing cutting-edge developments. Specific medication should strictly follow medical advice; non-medical advice does not constitute any investment advice.