Biobanking concepts at the hospital

Precision medicine comprises the entire patient path from screening via diagnostics, therapeutics and therapy monitoring up to prognostication for a single patient. Hereby, treatment decisions will not only rely on clinical routine diagnostics or tests that are currently reimbursed by public healthcare systems but more and more on all available data of an individual patient including molecular characteristics.^1–3

 

The molecular phenotype is reflected by biomarker compositions in the patient’s tissue and/or body fluids (for example, blood, urine) and can be elucidated using different OMICS techniques (for example, genomics, pharmacogenomics, transcriptomics, proteomics, metabolomics, and/or microbiomics). Depending on the patient’s clinical presentation, one or the other technique might be preferentially applied. 

 

However, for precision medicine it becomes increasingly important to build systems medicine-based therapy guidance upon several OMICS analyses per patient.^4,5 All OMICS techniques have in common the need for high quality sample input while each analysis technique has its own specific requests for sample preparation and quality assessment. Furthermore, identification and validation of disease-specific biomarkers by systems medicine not only relies on high quality biospecimens but also on corresponding comprehensive clinical data. Both can be provided by biobanks. 

 

The term ‘biobank’ describes a collection of human biological material (for example, tissue, blood, urine) and analytes thereof (for example, DNA, RNA, proteins, circulating tumour cells), which are linked to sample and donor-specific data as well as sociodemographic information about the donor.⁶

 

Depending on the material and data collected, the European, Middle Eastern & African Society for Biopreservation & Biobanking (ESBB; www.esbb.org) divides different types of biobanks: Museum-, Environmental-, Population-based-, Cell culture-, Therapeutic-, and Hospital-Integrated Biobanks (HIBs). HIBs seem to be the most challenging type since sample and data processing has to be implemented into the clinical setting without delaying routine treatment. Still, HIBs need to account for sample integrity, data protection laws and ethics. In addition, state-of-the-art HIBs are highly cost intensive. 

 

Why are HIBs then becoming more and more popular? The value of HIBs for enabling both translational research and precision medicine has been increasingly recognised: until now, only a few examples exist where research results could be successfully used for clinical implementation while the rate of FDA approved tests compared to the multitude of biomarker publications is devastating.⁷

 

One reason has been the overall low quality of clinical samples provided for translational research. Sample integrity can easily be affected by pre-analytical conditions such as time and temperature. However, about 70% of publications addressing biomarker research do not give information on sample collection and processing. 

 

This makes it impossible to judge the quality of the samples and hence the research results obtained by using such samples. Therefore, the International Society for Biological and Environmental Repositories (ISBER; www.isber.org) has established the SPREC reporting system (Standard PREanalytical Code) for controlling the main pre-analytical factors affecting clinical fluid and solid biospecimens.⁸

 

However, there is still no consensus on, for example, processing steps or storage temperatures for every type of sample used for biomarker studies.^9,10 Therefore, identifying and evaluating pre-analytical influencing factors such as temperature during processing and storage, freeze-thaw cycles, or manual versus automated processes have become a new research field: biospecimen research. Against this background it is common understanding that sampling, processing, and storage of biological materials need to become more standardised and quality assured as it has been practiced in the past. 

 

Fig. 1: Hospital Integrated Biobanks as an integral part of today’s and tomorrow’s healthcare and research systems for enabling precision medicine.

 

As a consequence, Biobanking developed to a new innovative discipline. The scientific societies ISBER and ESBB as well as BBMRI-ERIC (Biobanking and Biomolecular Resources Research Infrastructure under the European Research Infrastructure Consortium; www.bbmri-eric.eu) aim for harmonisation and interconnectivity of biobank processes in order to allow comparable sample quality across biobanks worldwide.^11–14 ESBB denotes at least six areas of responsibilities that all types of biobanks need to address:

 

1. Biospecimen research 

Analysis of any pre-analytic influencing factors for sample integrity covers the entire sample process from sample retrieval at the patient’s site via sample transport to the laboratory, sample processing (for example, centrifugation, aliquoting), up to sample conservation (for example, snap-freezing), sample storage and sample retrieval. Since many influencing factors have not yet been fully explored, it is fundamental to report on sample handling as precise as possible for which SPREC (see above) should be regarded as minimum information.

 

2. Cryo-biology 

Effects of pre-analytic variables (particularly due to storage at temperatures below the glass transition point of water at –135°C) on subsequent viability and functionality of intact cells need to be evaluated. This research is especially important for regenerative medicine applications.

 

3. Quality management (QM) and quality control (QC)

The entire biobanking process from patient recruitment through sample/data storage up to biomaterial request processing must run on standard operation procedures (SOPs) and fully comply to national and international guidelines, for example, ISBER, ICH-GCP for clinical trials, Good Laboratory Practice, OECD guidelines on human biobanks, genetic research databases and biological resource centres (www.oecd.org), the International Cancer Genome Consortium (www.icgc.org), and recommendations of the European Council on research with human material. Today, no international norm exists for QM systems that are particularly fit for biobank needs. 

 

However, the ISO 9001 norm has been increasingly adopted by biobanks in Europe since it reflects many aspects of biobanking management. Momentarily, ISO (International Organization for Standardization) is working in cooperation with national standardisation organisations on the development for a specific norm to standardise biobanks on an international level.

 

4. Information technology (IT)

The value of biomaterial only emerges through linkage with clinical data. This is one major task of a biobank information management system (BIMS). Not trivial but mandatory for high quality maintenance and sustainability are automated interfaces between BIMS and the hospital information system (HIS), laboratory equipment (robotics) and automated sample storage systems. 

 

The operational level of a BIMS can be divided into two major parts: within the clinical setting (highest data protection: militarised) and within research context (de-militarised zone). The biggest challenge is the interconnectivity between the militarised and de-militarised zone: the IT infrastructure must adhere to data protection laws and enable strict user and access rights to prevent misconduct. Due to this enormous challenge, many biobanks operate within the research setting – outside the clinical context – and therefore only receive pseudonymised patient data along with the biosamples. 

 

This concept only allows for obtaining samples and corresponding data at a given time and makes it difficult to acquire follow-up data/samples of the same patient electronically. Conversely, particular follow-up information is mandatory to explore if a given treatment has succeeded or failed.

 

This dilemma can only be overcome with an advanced IT infrastructure with separated databases for clinical patient annotations, patient identification data, and sample metadata sample storage information that can only be linked through a data custodian. Such a concept functions if a patient always visits only one clinical centre. When treated at different clinical sites, data protection laws in some European countries would make the use of a master patient index instance inevitable in order to link data from the same patient. 

 

Most importantly, the IT infrastructure should not only allow sample and data ‘export’ from clinic into research but should also offer a ‘feedback loop’ of research results to the clinician (Figure 1).

 

Only HIBs with according services will motivate clinicians to provide samples and data that are needed by biomedical researchers. One practical approach would be a BIMS operating in parallel to the HIS using similar access rights for the clinician whereas researchers internally and externally only see pseudonymised or anonymised data, respectively.

 

This allows clinical ‘real-time’ data in the BIMS located in the militarised zone, which then can be provided in a pseudonymised/anonymised form to researchers. In addition, HIBs’ IT infrastructure should also enable interfaces with other BIMS systems and/or metadata repositories.

 

5. Equipment infrastructure

HIBs require a wide interdisciplinary infrastructure comprising a sample reception area, a tissue and liquid sample processing laboratory, office space, storage capacities for consumables and informed consent documentation, and storage capacities for manual and/or automated storage systems for biosamples at room temperature, 4°C, –20°C, –80°C and/or nitrogen-based sample storage below –170°C; the latter one being especially required for downstream proteome/metabolome analyses. Working with liquid nitrogen requires special safety measures such as oxygen monitoring and exhaust air systems for potential nitrogen leakage. Electronic access and entry systems to the HIBs facilities should be obligatory to prevent unauthorised access.

 

Fig. 2: Automated sample process of ICB-L, exemplary showing (top left) incoming blood samples, (top right) automated and standardised processing of samples, (bottom left) transport of processed samples while maintaining the cooling chain, and (bottom right) data-logged storage of samples in nitrogen.

 

6. Ethical, legal and social issues

Patient’s informed consent (IC) is mandatory before any data or sample can be obtained. The optimal scenario would be an IC procedure that is most transparent for the patient while giving a broad generic consent for future biomedical research use. The IC procedure should be closely interconnected with use and access rights of the BIMS and be an integral part of the local data protection concept. Information brochures, video streams, newspaper articles and information events for the public should promote public awareness and information on biobanks.

 

These six areas of responsibility are highly interdisciplinary and particular labour and cost intensive. It can be easily envisioned that such tasks can only be achieved at high level through centralised biobanks. Serving more than 40 clinical disciplines at the Campus Lübeck, the Interdisciplinary Center for Biobanking-Lübeck (ICB-L; www.icb-l.de) has been established as central biobank infrastructure of the University of Lübeck (www.uni-luebeck.de), the University Medical Center Schleswig-Holstein (UKSH; www.uksh.de) and the Fraunhofer Institute for Marine Biotechnology (EMB; www.emb.fraunhofer.de). 

 

ICB-L operates on a strict governance concept with internal and external advisory boards, an executive committee as well as use and access regulations for biobank members and external requests. ICB-L is DIN EN ISO 9001:2008 certified and uses a three-stage broad and generic IC procedure allowing sharing of samples and data for biomedical research projects with collaborators in academia and industry worldwide. 

 

Automated interfaces between HIS and the central BIMS allow automated patient recruitment for research studies and clinical trials. While the BIMS runs fully operational in the militarised zone using a campus-wide harmonised data set of more than 1800 clinical and research parameters, double pseudonymised data are selectively transferred through a data custodian to extern accessible sample and data query tools such as CRIP (www.crip.fraunhofer.de), the Fraunhofer Metabiobank (https://metabiobank.fraunhofer.de), and/or the i2b2 query tool of the North German Tumor Bank of Colorectal Cancer (www.northgermantumorbank-crc.de).¹⁵

 

Together with its biospecimen research agenda, sample process automation and specialisation on automated nitrogen-based cryo-conservation, ICB-L allows for highest sample quality while guaranteeing a fully closed cooling chain. ICB-L has become test-side for cryo-technology and IT solutions, runs a training programme for graduate students and undertakes consulting activities for academic and industry partners regarding HIB related processes.

 

Centralisation by itself is a major challenge for HIBs – particularly within the clinical setting: all processes need to be standardised and quality-assured. However, the clinical setting does vary substantially from one clinical discipline to another, from in- to outpatients, and from individual staff members having different roles and rights along the patient’s clinical path. 

 

Hereby, data protection laws, ethical approval and patients’ IC are mandatory issues to be addressed, while at the same time biobanking cannot interfere or delay clinical care.   

On the other hand, HIBs offer the unique possibility to enable precision medicine. HIBs are particularly predestined to close the infrastructural gap between routine patient care and translational research. 

 

Through this unique role, HIBs enable research with high quality biosamples and corresponding clinical phenotype data. This is the only basis for gaining innovative and clinically relevant results. Furthermore, HIBs play a fundamental role in returning research results back into the clinic so that the clinician in charge can access actual research results for her/his individual patient in order to choose the individually best possible treatment regime. 

 

Such scenarios can reach from molecular imaging-based planning for complex surgical interventions to molecular tumour boards in which the interdisciplinary team of physicians also considers OMICS-based systems medicine therapy guidance. The latter scenario is partly established for patients resistant to first- or second-line therapies at major healthcare providers. In the broadest sense, HIBs can help to yield the best possible clinical knowledge gain for an individual patient.

 

In summary, medical advancement can hardly be envisioned without hospital-integrated biobanks; precision medicine will be strongly limited without them. HIBs should therefore be considered as an integral part of today’s and tomorrow’s healthcare and research systems, become established Europe-wide and not be limited to academic university hospitals. While connecting translational research with clinical routine for enabling precision medicine, sustainability of HIBs should be assured by both research funding and healthcare revenues.

 

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