Biobank Networking: The European Network Initiative and the Italian Participation

Introduction

Human biological samples including associated medical data and biomolecular research tools are a key resource in unraveling the interplay of genetic and environmental factors causing diseases and impact on their outcome, identification of new targets for therapy, drug discovery, and development. The biomedical research community increasingly recognizes the importance of high-quality, well-annotated biospecimens for the future success of molecular medicine. Biomedical quality-assessed samples and data as well as biomolecular resources and molecular analysis tools are essential for academic and industry-driven research to treat and prevent human diseases. However, numerous collections of biological materials have been established spontaneously by researchers, utilizing different preservation procedures. As a result, the stored samples are often of uncertain biological characteristics and may have little utility. Collections, no more spontaneous, but organized and structured according to common and shared rules, become indispensable for obtaining statistically significant and relevant results.

The European Strategy Forum on Research Infrastructures, a strategic instrument of the European Council, has the task of developing the scientific integration of Europe and to strengthen its international outreach. The publication of the first Roadmap for pan-European research infrastructures in 2006, as well as the implementation report in 2009, ¹ recognized the growing need for harmonized approaches to establish and manage biorepositories and for the implementation of a European infrastructure, built on existing sample collections, resources, technologies, and expertise, connecting them in a network.

The European Commission financed the preparatory phase of the Biobanking and Biomolecular Resources Infrastructure (BBMRI), ² structured as a federated network of biological resources centers including all types of repositories of biological materials of human origin: disease-oriented, population-based biobanks and biomolecular resources; it includes all fields of medical research: rare diseases, cancer, complex diseases, population-based biobanks for epidemiological studies, etc.

BBMRI has the following objectives:

- harmonizing standards for sample collection, storage and analysis,

BBMRI, during the preparatory phase, established an interactive catalog of associated biobanks—>250 centers from 21 European countries. The biobanks in the catalog provide>16 million samples. ³

BBMRI, in planning since January 1, 2008, is now approaching the operative phase, with a central management office in Austria and common services in other member countries. These central units will link to national hubs for coordination across Europe, which will in turn connect with the numerous national biobanks, hospitals, and institutions.

European Research Infrastructure Legal Status

To facilitate the establishment and operation of research infrastructures, the European Council issued the so-called European Research Infrastructure Consortium (ERIC) regulation, ⁴ a common legal framework for an ERIC. ERIC is a legal entity with legal personality and full legal capacity recognized in all EU member states. Its basic internal structure is very flexible, leaving the members to define the statutes, case by case, membership rights and obligations, the bodies of the ERIC, and their competence.

The application for BBMRI legal statutes shall be submitted to RTD-ERIC@ec.europa.eu by the host member state on behalf of all future members of ERIC. Any member state may be represented by one or more public entities with a public service mission. Each member of the ERIC shall contribute to its budget.

The application is valid if it is supported by at least 3 member states and shall contain the following: (i) the proposed statutes of the ERIC, (ii) the technical and scientific description of the infrastructure (business plan), (iii) the declaration of the host member state recognizing the ERIC as an international organization exempted from VAT and excise duty according to the pertinent directives, and (iv) the agreement between the members of the ERIC on the limits and conditions of the tax exemption.

The ERIC may carry out limited economic activities, which means according to the EU Commission that the share of economic activities shall be no more that 25% of the total annual activities. If an economic activity becomes so successful to be no longer considered limited, the ERIC may create a spinoff company.

In the case of a distributed infrastructure, as planned for BBMRI, with a central hub coordinating several distribution facilities, the central hub has to assure the following: (i) the definition of the overall strategy and common standards, (ii) the provision of joint training and technology transfer agreements, and (iii) the establishment of an appropriate mechanism of joint evaluation and peer reviews of the activities.

BBMRI-ERIC Statutes

The necessity of keeping the organization of BBMRI as simple as possible, to adapt it to future needs, within the constraints posed by the ERIC regulation was well addressed in preparing the draft statute of BBMRI-ERIC.

The statutes identify the assembly of members and the director general as the governance bodies of BBMRI-ERIC.

The assembly, composed of all members of the BBMRI-ERIC, is the means by which the members will make decisions on all matters pertaining to the infrastructure, which will then be implemented by the director general. The assembly appoints within its members a finance committee, with the responsibility of advising the assembly and the director general on matters relating to financial planning, preparation of budget, expenditures, and accounts.

To expedite the functioning of the central hub, the assembly, between its sessions, will be represented by the governance board. The governance board will operate within the mandate setup by the assembly and will be composed of the chairman and vice chairman(s) of the assembly and the finance committee.

The director general, selected and appointed by the assembly, for a definite period of time, is an employee of BBMRI-ERIC; he/she will be assisted by the staff of the central hub and by the management committee.

The central hub will be linked to the national node in each participating member state. The national node ⁵ is an outpost of BBMRI-ERIC, which interfaces with the national, regional, or thematic network(s) of biobanks and coordinates its activities with those of the central hub. Each national node has a director, appointed by the appropriate authority of the member state as the national BBMRI-ERIC coordinator.

The national coordinators participate in the operational management of the infrastructure as members of the management committee.

The activities of BBMRI-ERIC shall be periodically evaluated by an independent scientific and ethical advisory board (SEAB), composed of scientists appointed in their own right and not as representatives of the member organizations. The assembly appoints the SEAB members, based on the SEAB terms of reference and rotation. The SEAB advises the assembly on the appointment of the director general and on the work programs.

The Technical and Scientific Description of the BBMRI-ERIC (Business Plan)

The mission of BBMRI-ERIC is to construct a sustainable infrastructure, capable of providing access to biological collections and delivering services to the biomedical research community, from both the public and private sectors, through a central user interface. The construction and operation phase of BBMRI-ERIC will be mainly and sustainably funded by the participating member states, but part of the costs will be also recovered through a user's fee and additional funding acquired from projects of EU or national sources.

BBMRI-ERIC will adopt a flexible hub and spoke model. The central headquarters will be linked to biobank partners and will work in collaboration with the national nodes, which in turn is connected with national biobanks networks and biobanks of research institutions. Common services are planned, as part of BBMRI-ERIC, to support the work of the biobanks in the following fields: population-driven studies; case-related studies; bioinformatics; ethical, legal, and social issues; and bimolecular resources. For each of these fields, common services will be established following a call for tenders' procedures. It is expected, because of the return of the investment, that institutions selected for hosting a common service, will contribute to its total costs either in cash or in kind.

The market forecast for pharma and bioindustry, working in the fields of biomarkers, diagnostics, and biotechnology tools, predicts an increasing demand for access to high-quality human biological samples and associated medical data. The critical unmet need for the development of new drugs is the access of pharma to cohorts of individuals with well-characterized differences in disease progression and treatment outcome. This access poses the challenge of linking biospecimens to multiple sources of healthcare information while protecting the stakeholders. ERIC-BBMRI will reconcile the altruism of sample donation with an open collaboration with industry, involving issues of profit and intellectual property rights by identifying expert centers.

The expert centers are biorepositories of public institutions, capable of generating from the collected samples the data necessary to industry for its development goals. The expert centers will keep the detailed clinical data and the related biospecimens with the clinicians and scientists who generated them and have established a personal relationship with the study subjects and the local culture. Moreover, the expert centers have the ability to recontact the research subjects to obtain additional biospecimens if needed. To preserve the confidence of the public on the capability of the biobank acting for the common good, the expert centers will place the results in the public domain with no intellectual property claims that will obstruct the subsequent use by public or private parties.

The Italian Participation in BBMRI

At present, 40 biobanks, with the number increasing, are associated with BBMRI, some of them as both individual organizations and thematic networks. The networks participating in BBMRI have been established with the goal of sharing samples and data to strengthen the instruments available to researchers.

Italian Thematic Networks Built in Response to the Initiative of BBMRI

A call for the organization of prototype networks based on national networks, organized as hubs of thematic biobanks, was launched by BBMRI in June 2009. The goal is to scale up the prototypes to a fully working infrastructure after the implementation of the BBMRI-ERIC legal entity. In coherence with the distributed hub and spoke architecture of BBMRI, the national node (ISS) in October 2009 presented 6 networks as members of the BBMRI prototype. ²⁰ Two of them, VAS ⁷ and RIBBO, ⁹ have already been described, and the others were the Italian Network of Genetic Isolates, the BBMRI-Multispecialty Hospital Biobank prototype, the Network of Italian Pathology Biobanks, and the da Vinci European Biobank (daVEB).

The Italian Network of Genetic Isolates, coordinated by Prof. Paolo Gasparini of the University of Trieste, has the aim to analyze complex and quantitative traits responsible for diseases by establishing a network of studies on genetic isolates.

The Multispecialty Hospital Biobank prototype, coordinated by Prof. Paolo Rebulla of Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, proposes an operational model of hospital-networked biobanking connected with a national hub.

The Network of Italian Pathology Biobanks, coordinated by Prof. Giorgio Stanta of the University of Trieste, will improve the availability of histological classified human tissues for translational research and validation and standardization of diagnostic, prognostic, and therapy-predictive biomarkers.

DaVEB, coordinated by Prof. Pierluigi Rossi Ferrini of the University of Florence, is in the process of becoming a regional hub with a centralized IT infrastructure and a main repository serving several research groups.

The Organization of Italian Regional Networks

The Italian Government and the regional authorities adopted on March 25, 2009, a common decision stating that a biobank is a “service unit, located within public or private health facilities, not directly for profit, aimed to the collection, processing, preservation, storage and distribution of human biological material for diagnostic investigation, research, and therapeutic use.” ²¹ The same co-decision has earmarked EUR 15 million for the regional authorities to implement 3 types of collections, specifically cord blood biobanks, devoted exclusively to transplant activities, and 2 types of biobanks for research, muscle-skeletal biobanks and oncology biobanks.

Some regional authorities have already implemented the co-decision in different ways; others are in the process of building their networks.

The Provincial Health Authorities (Azienda Provinciale per i Servizi Sanitari) of the Autonomous Province of Trento has established the Trentino Biobank, which is in charge of the collection and storage of human biological materials for scientific research purposes at the Operative Unit of Surgical Pathology of the S. Chiara Hospital of Trento. ²²

In Tuscany, the daVEB ²³ is now a main repository storing 27 diverse collections for several research groups, operating in the Florence and Pisa areas, and acting as a centralized IT infrastructure for other groups working at the Universities of Siena and Pisa and is a de facto regional hub.

Regione Liguria ²⁴ has formally recognized the regional biobanks in its territory, which collect and distribute samples for research: (a) acknowledging that the donation of organs and tissues for both research and diagnostic use have a high social and economic value; (b) addressing the need to establish a network of regional biobanks, which form part of the project BBMRI. Regione Liguria has recognized the following biobanks as relevant for the regional health system: the Galliera Genetic Bank ²⁵ of the Human Genetic Laboratory at Galliera Hospital in Genoa, which collects samples from cases of human genetic diseases; the IRCCS Giannina Gaslini, which, as a Pediatric Biological Resources Center, also collects biological material from patients suffering from genetic illnesses ²⁶ ; the Cell factory and Biobank of the Istituto Nazionale per la Ricerca sul Cancro di Genova^27–29 ; and the Genoa Tissue Bank, the bank of Pathological Anatomy at the University of Genoa, Hospital San Martino. ³⁰

The biobanks of Galliera and Gaslini Hospitals are both members of the Telethon Foundation network, ⁶ and the Cell factory and Biobank of the Istituto Nazionale per la Ricerca sul Cancro di Genova ¹⁴ is a member of the RIBBO network. ⁹

A virtual bank of biological material has been created by the Lombardy Region, to further develop research for cancer care. The project leader is the National Cancer Institute, ³¹ which under the supervision of Maria Grazia Daidone has activated the Rete oncologica lombarda. ³²

A national network of the population-based biobanks will be the result of the collaboration between the Ministry of Health and the regional authorities, through the CCM, the Italian acronym for the National Center for Disease Prevention and Control. Its task is to liaise between the Ministry of Health and the Regional Governments in the fields of public health surveillance, prevention, and prompt response to emergencies. In 2010, the CCM issued a call for proposals, directed to public health institutions for building a national network of population-based biobanks. ³³ The winner of the call was the ISS with the project “Construction of the Italian hub of the population biobanks.” The network under construction comprises the population-based biobanks, described earlier, and the Institute of Medical Genetics of the European Academy of Bolzano, ³⁴ which, under the supervision of Dr. Pramstaller, will collect samples from 15,000 individuals living in the Venosta Valley of Bolzano Province.

The Italian Node of BBMRI-ERIC

The BBMRI-ERIC draft statutes require the creation of the Italian node organizing and managing the single biobanks as well as the regional and national thematic networks.

Prof. Ferruccio Fazio, Minister of Health, aware of all these initiatives, both at the national and European level and certain of the importance for the Italian researchers to participate in BBMRI, wrote to Prof. Enrico Garaci, president of the ISS, “to undertake the necessary steps for the constitution of the Italian National Node of BBMRI to coordinate the participation of the biobanks, so as to enable the country to offer a significant contribution to the achievement of this important European infrastructure.”

Dr. Elena Bravo was appointed as coordinator of the national node with the task of implementing the Minister of Health's instructions and she now faces the challenge of creating a virtuous collaboration among scientists managing their biobanks, the thematic networks, and also the regional authorities developing different models of regional networks.