The role of the pathologist in tissue banking: European Consensus Expert Group Report
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Human tissue biobanking encompasses a wide range of activities and study designs and is critical for application of a wide range of new technologies (-“omics”) to the discovery of molecular patterns of disease and for implementation of novel biomarkers into clinical trials. Pathology is the cornerstone of hospital-based tissue biobanking. Pathologists not only provide essential information identifying the specimen but also make decisions on what should be biobanked, making sure that the timing of all operations is consistent with both the requirements of clinical diagnosis and the optimal preservation of biological products. This document summarizes the conclusions of a Pathology Expert Group Meeting within the European Biological and Biomolecular Research Infrastructure (BBMRI) Program. These recommendations are aimed at providing guidance for pathologists as well as for institutions hosting biobanks on how to better integrate and support pathological activities within the framework of biobanks that fulfill international standards.
KeywordsPathology Biobanks Biomarkers Harmonization Standards Translational research
Over the past 20 years, biobanking of human specimens has become a central activity underpinning all aspects of biomedical research as well as the development of personalized medicine [1, 2, 3, 4]. Biobanking encompasses a wide range of specimen types and sample collection designs, ranging from population-based biobanking of specimens from healthy subjects in large, epidemiological cohorts to specific biobanking of diseased tissues obtained in the course of clinical interventions [2, 5, 6, 7]. Human tissue biobanking is of particular importance for implementation of novel biomarkers into clinical trials, as well as for the application of a wide range of new technologies (-“omics”) to the discovery and validation of new, molecular patterns of disease [8, 9, 10, 11, 12].
Heterogeneity and variability of pre-analytical practices is a major source of error in analyzing biobanked specimens. In recent years, large international efforts have converged towards the harmonization of standard operating procedures for biobanking, providing a basis for improving reproducibility and comparability of molecular data as well as for designing large, multicentric studies involving specimen exchanges among different centers [4, 13, 14, 15, 16, 17].
The most critical steps in the workflow of biospecimen acquisition and annotation for biobanking involve hospital pathologists. Pathology is the cornerstone of tissue biobanking. The most basic minimal standard for any biobanking operation is to identify and define the nature and origin of the tissues to be kept in the biobank. This requires specialized pathology expertise. Furthermore, pathologists also make decisions on what should be biobanked, making sure that the timing of all operations is consistent with both the requirements of clinical diagnosis and the optimal preservation of biological products. Pathologists also play a central role in the design of studies involving banked biospecimens and in the dialogue between clinicians and researchers. The rapid development of biobanking as an essential process in translational research and personalized medicine places strong demands on the work of the pathologist.
This document summarizes the conclusions of a Pathology Expert Group Meeting that took place in Munich in December 2008 within the European Biological and Biomolecular Research Infrastructure (BBMRI) Program [4, 18]. The experts have considered all aspects of the involvement of the pathologist in the biobanking process. They also discussed the impact of biobanking on pathology practice. The recommendations developed in the document are aimed at providing guidance for pathologists as well as for institutions hosting biobanks on how to better integrate and support pathological activities within the framework of biobanks that fulfill international standards.
Scope and definition
The focus of the working group is the banking for research of human tissues in a clinical context. This activity is hereby defined as “tissue banking”. It includes, but is not limited to, the banking of residual specimens obtained in the course of clinical procedures as well as of “post-mortem material.”
Tissue banking is a chain of operations that includes informing patients and obtaining the proper consent (depending on local requirements), data acquisition, tissue procurement, annotation, preservation, storage, quality control, cataloguing, managing of access, processing and distribution. Pathology expertise is required at several steps. Tissue banking also requires expertise in cryobiology, quality management, legal/ethical aspects, project management, staff management, administration and networking.
“Pathology archives” represent a special type of tissue repository that may support tissue banking, provided that they fulfill required standards with respect to (1) documentation of variations; (2) cataloguing; (3) rules of access; (4) fulfillment of legal requirements for use as research resource. The primary role of these archives is to document diagnosis and to support later/metachronous diagnostic analyses but they should be developed in a way that allows them to fulfill roles in research as well.
R1: The working group recommends developing a published reference framework for “organizing and managing a tissue bank” in clinical practice, defining standards that distinguish “archive” from ‘tissue bank”.
R2: In the accreditation process of a pathology laboratory, the quality and compliance to standard of the tissue archive/tissue banks must be taken into consideration.
Tissue banking: critical role in articulating translational research and personalized medicine
Tissue banking in a clinical context is essential for the procurement of high quality samples for translational research aimed at biomarker discovery and validation as well as identification of new targets for therapy. It is therefore a strategic activity for research and innovation in biomedicine.
Tissue banking is critical for implementing and applying biomarkers in clinical practice. It lays the foundations for the discovery of new targets for therapy and for drug discovery. It sets conditions and procedures allowing patients to benefit from new developments in biomarkers as well as personalized medicine and is therefore beneficial for future diagnosis and treatment and for public health. In this vision, each patient contributes to the care that will be provided to the future patients.
Translational research on biomarkers encompasses three overlapping phases: discovery, validation, and implementation. Each phase has different requirements in terms of tissue banking.
Discovery phase is aimed at identifying biomarkers and molecular targets for therapy, establishing their prevalence and formulating hypotheses on their biological and medical significance in ex vivo analyses. This requires access to well annotated and pathologically reviewed case series, either based on specimens collected and processed in the course of clinical diagnostic activities or in specific tissue collection protocols.
Validation phase is aimed at demonstrating the effect and significance of a potential biomarker. This requires applying ex vivo analyses within study designs with adequate epidemiological and statistical power. Such designs may be comparable to those of clinical trials except that they do not necessarily imply de novo specimen collection using invasive procedures. In a number of cases, these studies can be constructed using retrospective or prospective collections.
Implementation phase is aimed at translating biomarkers into clinical practice in affordable, cost-effective conditions and at integrating new biomarkers into diagnostic practice. This requires applying biomarkers to a large series of specimens collected using standard operating clinical protocols.
R3: Contributing to medical progress through participation in tissue banking should be offered to the largest possible number of patients.
R4: Tissue banking should take into consideration the need for collecting appropriate reference samples. Whenever possible and appropriate, the reference sample may consist of corresponding tissue not affected by the disease process.
R5: Clinical practice should evolve to take into account the most effective way to exploit new molecular validated biomarkers and therapeutic targets. This requires technical innovation on evidence-based protocols for tissue procurement, preservation and processing. Innovation should also aim at better using archived collections.
R6: Given that specimens collected in clinical practice are critical for research, rules of patient information and consent should be compatible with the broad use of such specimens in conditions fulfilling strict criteria of protection of persons and data. The working group recommends that further work is developed to increase awareness on these issues and to develop ethical and legal procedures at the national and European level.
Role of the pathologist
The pathologist has an essential role in tissue banking. His medical and scientific expertise is required at two distinct phases in the process of tissue banking: (1) in making diagnostic decisions, providing specific annotations and overseeing specimen procurement and preservation, and (2) in reviewing specimens and providing information prior to specimen processing and distribution to research laboratories.
Through his role in tissue banking, the pathologist is a key actor in the continuity between research and medical care.
The pathologist adds value and expertise to the definition of the banked tissue and is a critical scientific contributor to research carried out on the specimen.
The pathologist validates the appropriateness of the banked tissue specimen and its use for a particular research purpose, excluding conflicts with diagnostic purposes.
The pathologist has a key role as custodian of the banked specimens. Tissue collections are best developed in the context of a pathology department or pathology service.
R7: No tissue banking for research should take place without proper pathology documentation. All specimens used within research programs must have been reviewed and assessed by a pathologist.
R8: The standard for tissue banking is a tissue sample and not derived products or isolated molecules.
R9: The pathologist should have an active participation in decisions of access to banked specimens.
R10: Efforts should be made to better communicate the role of pathology in tissue banking.
Role of institutions
Tissue banking is not the exclusive responsibility of pathology departments. It should be run in the context of institutions (mainly hospitals or universities) that are responsible for providing the whole chain of expertise and the organizational frame required for tissue banking.
Institutions are responsible for the maintenance, sustainability, and accessibility of tissue banks, adequate level of training of the staff and the protection of patient rights. Full cost calculation is an essential step in guaranteeing the sustainability of the tissue bank.
R11: Institutions should commit adequate resources and staff dedicated to acquisition, processing and proper distribution of both data and specimens and assisting the pathologist in all tasks that do not require a qualification in pathology. The basic requirements are (1) daily and technical management, (2) data and specimen collection management and (3) expertise in biobanking ethics and law, and (4) networking biobanks. Biobank staff, depending on the size of the pathology department should include at least a tissue bank manager and a technician in addition to the pathologist. The institution should commit adequate resources for pathologists to be involved, in addition to their clinical task, in tissue-banking activities.
R12: Technical and pathology expertise should be provided by the pathology department; the added scientific value should be recognized.
R13: Institutional commitment and appropriateness of the level of resources dedicated to tissue banks should be considered as critical elements in the process of tissue bank accreditation, which could be part of a general hospital or pathology accreditation.
R14: The institution should be responsible for setting and publicizing the rules of access to tissue banks.
R15: The rights of the patients should be taken into account in the procedures and rules for access and use of the tissue bank.
R16: In granting access to tissue-banked specimens, a general principle of “minimal sample amount of tissue necessary for the project” is recommended.
R17: Each procurement of banked tissue for research should be formalized through a Material Transfer Agreement (the scope and content of this MTA is a matter for further elaboration at the European level).
R18: Funding agencies should be aware of the requirements of tissue banking before granting funds for a research project. Projects using banked specimens should specifically (1) provide assurance of the participation and support of the tissue banks; (2) consider the costs of specimen procurement and processing in relation with their specific research application.
R19: A European framework for the professionalization of tissue banking should be developed, e.g., through a teaching program at master level.
Tissue banking in clinical trials
Clinical trials offer a wide range of designs with added value for the discovery, validation and implementation of potential new biomarkers
Using biomarkers is critical for the interpretation of many therapeutic trials in particular for defining the characteristics of responders vs. non-responders.
In future medical care, biomarkers will become mandatory for allocating patients to appropriate therapeutic protocols.
The participation of a biobank into a clinical trial should obey to the same strict technical, legal, and ethical standards independently of the type of promoter, academic, or industrial.
R20: As a rule, tissue banking should be considered as an option in every clinical trial.
R21: The need for biomarker application and the possibility of using trials for biomarker validation should be taken into account in the statistical and logistical design of the trial.
R22: Pathologists should be involved in trial design.
R23: There should be a comprehensive registry in the tissue bank (ideally coupled to an institutional clinical trial registry system) of the tissue samples collected in the context of clinical trials.
Improving standards for tissue banking within clinical practice
There are technical differences in current standards for tissue processing in pathology practice and in tissue banking.
Many protocols used in tissue banking, e.g., for duration of fixation, optimal time for preservation and duration of storage, are mainly based on experience rather than evidence.
There is a need for more adequate markers of quality for the tissue-banking process for the qualification of banked tissue specimens for specific research applications.
Discovery, validation, and implementation of biomarkers and therapeutic targets in the clinics require a very large series of specimens with inter-laboratory comparison. Such studies need strong networking between dedicated platforms using harmonized, comparable protocols.
R24: Innovation in tissue banking should focus on reducing gaps between standards for clinical practice and for research, and on the development of biomarkers for the quality control of tissue-banking procedures
R25: The development of evidence-based protocols supported by published data should be a priority. Journal editors should be made aware of this priority and should solicit contributions to support this effort. Scientific journals should develop proper expert reviewing for the correct collection, handling and processing of human tissues forming the basis of published data.
R26: It is recommended that current European initiatives and programs that develop technical platforms for large-scale specimen analysis are duly reviewed, assessed, and “harvested” for developing models for future network development.
Incentives for increasing the participation of pathologists
Tissue banking is an important mechanism by which pathologists participate in generating and increasing knowledge in biomedicine.
In many instances, the involvement of the pathologist adds scientific value to the banked specimens beyond the requirements of routine diagnosis. This added value corresponds to an intellectual property.
Tissue-banking activities entail considerable costs and demands on pathology staff time.
R27: Efforts should be made to increase the awareness of the pathology community that (1) participating in research through tissue banking is part of their professional duties; (2) tissue banking is an instrument for managing the evolution of pathology work towards integration of biomarker analysis in clinical practice.
R28: Pathologists should be involved as scientists in developing the design of studies using banked specimens and in interpreting their results.
R29: The scientific involvement of pathologists should be acknowledged in publication authorship. This involvement may consist of specific diagnostic procedures and annotations at the time of specimen acquisition and/or pathology review before specimen processing for specific research purposes.
R30: Contributing to tissue banking should not compete with the performance of clinical pathology duties; therefore, sufficient time and resources should be committed by institutions to the performance of tissue-banking activities.
R31: In developing research on banked specimens, researchers should take into account the costs of the tissue-banking operation and should include these costs in grant applications.
Conclusions and perspectives: a strategic vision for tissue banking in Europe
Today, tissue banks have a key role in the process of biomarker and drug target discovery through the procurement of annotated specimens to innovative research programs. In addition to this research role, the use of cellular and molecular biomarkers is rapidly becoming a standard part of hospital pathology practice and of therapeutic decision schemes. Tissue banking is the key mechanism for pathologists to get involved in translating newly discovered biomarkers into clinical practice . Furthermore, tissue banking will rapidly become an intrinsic part of pathology requirements in the context of standard clinical care.
Given its strong linkage with clinical activities, tissue banking is best performed at the local level, and its sustainability requires investment in infrastructure at the local and/or regional and national levels, to avoid duplication of effort and achieve critical mass necessary to address major academic research programs, as well as to secure a strong position in addressing the needs of industry. Therefore, tissue banks must be organized in operational networks .
Implementation of biomarkers will require large networks interconnecting tissue banks, analysis and distribution platforms and several other data resources such as databases of clinical information and population-based disease registries. Biobank networks should have fully documented standard operating procedures, share tissue bank catalogues, and clear rules for access [19, 20, 21]. They should also be able to run research projects based on collections developed in several tissue banks. Such projects may be retrospective (using previously banked specimens) or prospective. Running the same, hypothesis-driven collection protocol through a large network of tissue banks that adhere to the same standards will allow assembling large case series addressing a wide range of clinical conditions. In developing such protocols, the diversity of European populations and ecological contexts is an asset for the design of sophisticated case–case comparison studies .
To achieve this vision, it is essential to perform innovative research on improving all aspects of specimen processing, including the development of quality controls applicable to retrospective collections. This requires a dedicated effort from funding agencies and from the scientific and medical publication community. Training of highly qualified tissue-banking professionals will increase the standards of tissue banking as well as the recognition of tissue banking as an integral part of biomedicine. This will also facilitate the development and dissemination of a corpus of harmonized, evidence-based tissue-banking procedures.
Conflict of interest statement
We declare that we have no conflict of interest.
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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