Pathology as the Cornerstone of Human Tissue Banking: European Consensus Expert Group Report

Abstract

Aside from ethical considerations, the primary requirement for usage of human tissues in basic or translational research is the thorough characterization of tissues. The second, but equally essential, requirement is that tissues be collected, processed, annotated, and preserved in optimal conditions. These requirements put the pathologist at the center of tissue banking activities and of research aimed at discovering new biomarkers. Pathologists not only provide information identifying the specimen but also make decisions on what materials should be biobanked, on the preservation conditions, and on the timeline of events that precede preservation and storage. This central position calls for increased recognition of the role of the pathologist by the biomolecular community and places new demands on the pathologist's workload and scope of scientific activities. These questions were addressed by an Expert Group Meeting of the European Biological and Biomolecular Research Infrastructure (BBMRI). While detailed recommendations are published elsewhere (Bevilacqua et al., Virchows Archivs, 2010, in press), this article outlines the strategic and technological issues identified by the Expert Group and identifies ways forward for better integration of pathology in the current thrust for development of biomarker-based “personalized medicine.”

Introduction

The biomolecular knowledge accumulated through descriptive and experimental research during the past 25 years has started to deeply modify the medical landscape, paving the road to “personalized medicine” in which each patient receives adapted clinical care, based on the molecular characterization of individual forms of diseases and on the identification of molecular alterations amenable to targeting by using a new generation of “smart drugs.” Reaching this new frontier requires that extremely well-defined and preserved human tissues are collected and made available, while preserving patient integrity, for basic and translational research as well as, in the longer term, for routine diagnosis and prognosis. The practical implementation of this process defines “tissue biobanking.”^1–5

Biobanking encompasses a wide range of activities, ranging from population-based biobanking of specimens from healthy subjects to specific biobanking of diseased tissues obtained in the course of clinical interventions.^6–9 For many years, these activities have belonged to distinct fields of biomedical sciences, namely epidemiology and pathology. This distinction is now outdated by the development of novel technologies applicable to large specimen collections and of logistical infrastructures for monitoring long-term disease occurrence in large populations.

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 stored in the biobank. This requires specialized pathology expertise. Pathologists also make decisions on what should be biobanked, making sure that the timing of all operations is consistent with the requirements of clinical diagnosis and the optimal preservation of biological products. This critical position in the biobanking process places unprecedented demands on all aspects of pathology practice, calling for a strategic view on how this profession will respond to the challenge, not only as “tissue providers” but also as essential participants in the design, performance, interpretation, and implementation of research.

This article summarizes the discussions of a panel of European Pathology Experts Group that took place in Munich, Germany in December 2008 within the European Biological and Biomolecular Research Infrastructure (BBMRI) Program.^10,11 This Expert Group developed detailed recommendations that have been published in Virchow's Archivs (Bevilacqua et al., 2010, in press). Here we briefly summarize the main opportunities, obstacles, and challenges identified by the working group and ways forward for better integrating pathology practice at the core of the biobanking process.

Pathology in tissue banking: role in articulating translational research and personalized medicine

Tissue banking in a clinical context is critical for developing and applying biomarkers in clinical practice. It lays the foundations for the discovery of new targets for therapy and for drug discovery. Moreover, 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 3 overlapping phases: discovery, validation, and implementation. Each phase has different requirements in terms of tissue banking. The 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. The validation phase is intended to demonstrate 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 with 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 collections. The implementation phase is designed for translating biomarkers for use in 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 prospective protocols integrated within standard clinical practice. Clinical trials offer a wide range of designs with added value for discovery, validation, and implementation of new biomarkers. In medical care, biomarkers are progressively taking a greater part in decisions for allocating patients to appropriate therapeutic protocols and will soon become mandatory.

The pathologist is the central actor of hospital-based tissue banking. Specifically, the pathologist's medical and scientific expertise are required at 2 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 this role in tissue banking, the pathologist is a key actor in the continuity between research and medical care. The pathologist is thus a critical scientific contributor to research carried out using the specimens.

The pathologist is also the designated expert as custodian of the banked specimens. Tissue collections are best developed in the context of a pathology department or service. However, tissue banking is not the exclusive responsibility of pathology departments. It should be run in the context of Institutions (mainly hospitals or universities) who 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.

Technical and logistical challenges

Tissue banking is a chain of operations, which 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. In addition to pathology, tissue banking requires expertise in cryobiology, quality management, legal/ethical aspects, data management, administration, and networking.

Heterogeneity of pre-analytical practices is a major source of error in analyzing biobanked specimens. Currently, this heterogeneity may be considered as the main obstacle for the development and implementation of robust molecular biomarkers. Many protocols used in tissue banking, for example, duration of fixation, optimal time for preservation, and duration of storage, are 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 very large series of specimens with inter-laboratory comparison. Such studies need strong networking between dedicated platforms using harmonized, comparable protocols. In recent years, there have been significant efforts toward the harmonization of standard operating procedures for biobanking, providing a basis for improving reproducibility and comparability. These efforts have emphasized the need for procedures based on evidence rather than practical experience, delineating a new field of research, Biospecimen Science.^6,10,12–16

Outlining ways forward: toward the recognition of biobanking as the foundation of molecular pathology

Recognizing the problem of heterogeneity in biobanking practice as the main current obstacle, 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.” In the accreditation process of a pathology laboratory, the quality and compliance to standards of the tissue archive/tissue banks must be taken into consideration. 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.

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. It is recommended that current European initiatives that develop technical platforms for large-scale specimen analysis are duly reviewed, assessed, and their expertise be used for developing models for future network development.

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 rights of the patients should be taken into account in the procedures and rules for access and use of the tissue bank. Each procurement of banked tissue for research should be formalized through a Material Transfer Agreement, the scope and content of which is a matter for further elaboration at the European level. The working group recommends that further work be developed to increase awareness on these issues and to develop ethical and legal procedures at the national and European levels.

Biobanking is not simply a research activity. Conditions and procedures are set by it and biobanking allows patients to benefit from new developments in biomarkers and is therefore beneficial for diagnosis and treatment and for public health. In this vision, each patient contributes to the care that will be provided to the future patients. Contributing to medical progress through participation in tissue banking should be offered to the largest possible number of patients. This, in turn, will drive clinical practice to evolve in providing the most effective way to exploit novel, validated bio-markers, and therapeutic targets. This translational activity takes place through clinical trials implementing biomarkers. As a rule, tissue banking should be considered as an option in every clinical trial, whereby the possibility of using trials for biomarker validation should be taken into account in the statistical and logistical design of the trial. It is recommended to consider the development of open registries of tissue samples collected in the context of clinical trials.

There is an urgent need for better recognition for the role of pathologists, not only in the biobanking process per se, but also in the process of translational research on biomarkers. No tissue banking for research should take place without proper pathology documentation. All specimens used within research programs must be reviewed and assessed by a pathologist. It should be kept in mind that the standard for tissue banking is a tissue sample and not derived products or isolated molecules. Conversely, the pathologist should have an active participation in decisions of access to banked specimens, and 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 and (2) tissue banking is an instrument for managing the evolution of pathology work toward integration of biomarker analysis in clinical practice. The bio-medical community should acknowledge the role of the pathologist as researcher, not only as tissue provider, but also including them in publication authorship.

Finally, none of the developments outlined here may take place without the commitment of clinical institutions of 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. 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. 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. As part the professionalization of tissue banking, the working group recommended the development of a European curriculum framework, for example, through a teaching program at master level. 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.

Funding agencies should be aware of the requirements of tissue banking before granting funds for research. Projects using banked specimens should specifically (1) provide assurance of the participation and support of the tissue banks and (2) consider the costs of specimen procurement and processing in relation with their specific research application. 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.

Conclusion

Strategic vision for hospital-based tissue banking in Europe

The perspectives outlined in this review clearly call for increased networking between clinical biobanks at regional, national, and international levels. However, 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 level. The grouping of tissues collected across multiple institutions into highly centralized biobanks would be counterproductive in loosening the essential ties between tissue collection, clinical practice, and patient's follow-up. Although it is often perceived that centralized biobanks would be easier to manage for research, they would delay the necessity for clinical centers to adapt their working procedures to the needs of today's and tomorrow's personalized medicine.

At the same time, it is vital 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.¹¹ Such networks should share standard operating procedures and tissue bank catalogs, and should publicize clear rules for access of researchers to biobanked specimens.^17–19 They should have the capacity to run joint, hypothesis-driven collection protocols to assemble 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.²⁰

To achieve this vision, it is essential to perform innovative research on improving all aspects of specimen processing and quality control, and to train highly qualified tissue banking professionals, who will increase the standards of tissue banking as well as promote the recognition of tissue banking as an integral part of biomedicine.

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