Broad donor consent for human biobanks in Germany and Europe: a strategy to facilitate cross-border sharing and exchange of human biological materials and related data

Introduction

Today, human biobanks have been recognized as important resources for medical research, in particular for the progress in targeted drug therapy [1], [2]. A “biobank” in the sense of the present article collects and stores human biological material and related data for often not foreseeable medical research purposes [3], [4], [5], [6], [7], [8]. Such research may comprise basic research as well as applied (clinical) research directed toward (i) a faster and more precise detection of diseases (diagnostics), (ii) a prediction of disease development and outcomes (prognosis), (iii) a more precise and efficient treatment (therapy) and/or (iv) avoiding factors/conditions resulting in (prevention of disease occurrence) or accelerating disease development (prevention of disease progression).

The majority of modern human biobanks currently (or will in the near future) strive for inter- or multidisciplinary co-operations and networking between single or multiple collections of human biological material with established governance and procedural rules, including access and sharing policies [1], [3], [9]. In the past two decades, such policies have been developed and successfully implemented in a variety of German population-based (KORA, SHIP, NAKO [10], [11], [12], [13], [14]) and – more recently – also in disease-oriented research networks (e.g. GANI_MED, DKTK, DZL, DZHK [15], [16], [17], [18]). With regard to sample access and sharing, German biobanks are bound to European, national and state laws. As a basic principle, irrespective of the site where biological samples and related data are ultimately used, the respective national law is applicable to the collection and processing of samples and data [19]. Current and future (not foreseeable) research issues often require cross-border exchange of biological samples and related data, but such processing of data and use of biospecimen must be compliant with the provisions of the donor’s consent (and/or – in exceptional cases – with the decision of an “independent competent ethics committee” [for definition, please see text box]) [20]. On this background, many of the internationally prevailing informed consents are inadequate because of their limitations to specific diseases or research objectives.

Hence, an expanded and – at the same time – cross-border-oriented scope is required, balancing individual donor rights and research interests [21]. Based on previous “best practice” models and the experiences with consent management and consenting procedures gathered in previous larger population-based studies (KORA, SHIP, GANIMED [10], [11], [12]), the biobank task force of the permanent Working Party of the German Medical Ethics Committees (WP-GMEC) has developed in 2013 [22] and recently updated [23] its master template for the “broad use of human biological material and related data for medical research”. The document focuses on large interdisciplinary clinical biobanks (associated, e.g. to university hospitals) and has been re-approved by the general assembly of all independent competent German medical ethics committees (see the following text box for definition) in June 2016.

Definition

The term independent “competent” ethics committees is specific for Germany and represents the generally accepted expression for currently 52 “public” ethics committees established based on federal state law (Landesrecht) situated at 36 German Universities (with Medical Faculties), and at each (federal) state’s Physicians Chamber (15 Landesärztekammern), and three (federal) state’s ethics committees (Länder Berlin, Bremen, and Sachsen-Anhalt). Competent ethics committees by definition must be independent, interdisciplinary, and following EU-regulation 536/2014 (adopted by Germany on December 20, 2016), as a minimum standard, must be composed of at least:

1. 1 lawyer/judge,

2. 1 ethicist,

3. 1 biometrician/statistician,

4. 3 clinically experienced physicians from different clinical disciplines, including one pharmacologist or toxicologist, and

5. 1 lay member.

Competent ethics committees in Germany are different from private ethics committees (e.g. the “Freiburger Ethikkommission”) or clinical ethics committees required in certain situations with critically ill patients in order to guide the treating physicians. Because competent ethics committees are installed by law and relevant stakeholders in the approval procedure for clinical phase I–III trials according to Medicines Law or Medicines Product Law, they are generally more powerful and often have more interdisciplinary and biometrical/statistical competence and experience than the internationally prevailing research ethics committees, the said “private ethics committees”, “clinical ethics committees”, “institutional research (ethics) committees”, “ethical and/or scientific review boards” (e.g. companies, biobanks from the pharmaceutical industry), and also differ from any “use and access committees” at biobanks and/or data warehouses.

The updated template acknowledges international requirements for consent in (human) biobank research [7], [24] and particularly fulfils the current Organisation for Economic Co-operation and Development (OECD) [25], [26], [27] and World Medical Association (WMA) recommendations [20] for biobanks. On this basis, it furnishes a framework that enables long-term storage and multi-purpose use of human biological material and related data, provided they are exclusively employed in biomedical research, including cross-border research. The following sections will serve to present this framework more in detail.

Ethical framework for a broad consent

From the perspective of a potential donor, the collection and storage of human biological material for medical research purposes always requires a clearly assigned purpose on an individual basis [21]. Consequently, the purpose of the collection, storage and intended use of human biological material and related data by a biobank should be specified as exactly as possible [28]. Such purposes might be, e.g. the conduct of a particular clinical study, or research focused on a specific disease (i.e. lung cancer) or well-defined disease entities (i.e. cardiovascular diseases or brain disorders).

On the other hand, biobanks must be prepared to satisfy future medical research objectives and meet future challenges in public health by permitting broad use of human biological material and related data, including cross-border exchange [8], [9], [19], [28]. The ethical framework should enable biobanks to fulfil their mission in (i) opening new vistas for medical research and (ii) supporting optimization of public health care. However, as a pre-condition for legal validity of a broad consent, the unpredictability of the future use of donated biological samples and related data must be compensated by appropriate measures and procedures [3], [4], [8], [9], [21], [25], [26]. In this regard, in Germany, independent competent ethics committees are of paramount relevance for both (i) the assessment of the human biobank itself (during set-up and during operation) and (ii) the assessment of individual research projects requesting “broad consent” biological samples as a general pre-condition for the release and delivery of such samples [8], [28], [29].

When asked for broad consent, the donor has to be informed unambiguously on the broad scope of the future use of his/her biological material and related data including the option of cross-border medical research. However, even under the conditions of “broad consent” the donor should be given, at least to some extent, the opportunity to exclude certain research fields and/or procedures from future use [21], [28] (similar but not identical to a so-called dynamic consent [30]). Finally, it should be noted that the “broad consent” proposed here is not unlimited but clearly restricted to biomedical research.

The tasks of ethics committees regarding human biobanks

Information documents and (broad) consent form for biobank donors

Besides public engagement and transparent processes of a biobank, one of the essential pre-conditions for the acquisition and storage of human biological material for multiple medical research purposes is the informed (broad) consent form, signed by the donor after comprehensive written and oral consultation [28]. When approached for biobank participation, many individuals/patients want to make an active and informed choice, but for altruistic reasons are also prepared and willing to consent broadly to future research use [34], [35]. The content of the information document should be easy to understand and as concise as possible (but at the same time as comprehensive as possible). The WP-GMEC text template “for the use of human biological material and related data in biobanks” in its current version represents a first (nation-wide harmonized) step in this direction and should thus serve as a model for all German human biobanks [23], [36]. If genetic analyses of human biological material are intended, this should be specified in the information and consent documents and addressed during oral consultation.

If foreseen, the predetermined procedures for feedback of incidental or unsolicited genetical (research [!]) findings should be communicated to the donor as well. Following the current version of the Declaration of Helsinki [32] (10/2013, §26), referred to also in the current WMA recommendations [20] (10/2016, §11), information and consultation of donors should be performed by the physician or another appropriately qualified individual (personnel) trained in biobanking, able to provide supplementary information and to answer questions pertaining to the consent.

The signed (both by donor and informing physician/qualified personnel) consent forms must be stored by the institution/hospital that has obtained the consent (or by a trusted third party [TTP], exceptionally by trusted biobank personnel [e.g. biobank office, secretary], having no access to any donor-related clinical data). The retention period of consent forms should last at least for the time period the biological material and related data will be stored and/or used for medical research purposes. A copy of the signed (broad) consent form and the information document must be handed to the donor [28].

The consent may also be obtained for long-term storage and multi-purpose use of the donor’s biological material and related data for medical research, as long as this has been explicitly stated in the broad consent form and during (oral) consultation. In any case, all permissions expire with the withdrawal of the consent by the donor [21], [28].

When the scope and intended purpose of a human biobank or any relevant conditions under which the consent has previously been obtained change, renewal of the consent is required – except if

1. a disproportionate effort to re-contact the respective donors has been made (e.g. the donor relocated and – even with the assistance of the respective registration office(s) – the new address cannot be established, or in case the donor is deceased and neither heirs nor family members can be identified, even with the aid of the appropriate authorities), and

2. the scientific interest and/or potential medical benefit of such changes outweigh the interests of the donor or any other person concerned [8], [9], [21], [28].

In all such cases, it is, however, recommended to obtain additional approval by an independent competent ethics committee – at least in Germany [28].

Already existing biological material and related data available from a deceased individual may be transferred into and stored in a human biobank only, if such material and related data are fully anonymized, or if the scientific interests outweigh the vested interests of the respective individual or any other (related) person concerned. In all such cases, again, approval by an independent competent ethics committee is strongly recommended [21]. Inherently it is virtually impossible to achieve full anonymization, particularly with regard to genetic information (e.g. of biological samples containing DNA) [37]. Usually, anonymization means that the connection between a pseudonym and the personally identifiable information of the donor/patient is deleted. If the donor/patient requests destruction of his/her biological material and deletion of all related data, the anonymization procedure must be carried out only after destruction of the biological material. Nonetheless, data cannot be removed from the analyses of already completed studies and/or published research results.

It should be noted, however, that any collection, storage and transfer of data related to human biological material in the context of research projects entails the risk of breach of confidentiality (e.g. the possibility of identifying the donor), in particular, with regard to genetic information even if it is anonymized. Therefore, the WG-GMEC “broad consent” template clearly states that these risks cannot be completely excluded, and that they increase with increasing amounts of linked data, particularly, when additional genetic information is made available by the donor/patient himself, e.g. in the internet for purposes of genealogy [23]. Human biobanks and/or associated data warehouses shall take all appropriate measures according to the current state of technology to protect the privacy of their donors, including an implementation of novel anonymization tools using algorithms for controlled tampering/modification of research data (e.g. by systematically adding or transforming relevant parts of the anonymized data [37]).

Data protection and pseudonymization

As a general rule, personally identifiable information should never be transferred to a biobank but rather remain at the institution (hospital/treating physician) where the respective data were collected. By this procedure, personally identifiable information are protected by medical confidentiality and any access for third parties is regulated and/or restricted by criminal law [27].

Conclusions

Nowadays, the openness of future medical questions and future challenges for public health besides specific research projects also requires broad, including cross-border, use of human biological material and related data. There is international [3], [4], [6], [9] and EU-wide consensus [5], [7], [8] that broad consent is ethically legitimate based on two key arguments: (i) opening new vistas for medical research and (ii) optimizing public health care [6], [8], [21], [24], [28]. However, in addition to public involvement and transparency of all governance processes of human biobanks striving for “broad consent” biospecimen collections, as a pre-condition for the legal validity of a donor’s broad consent, the unpredictability of the future use of donated biological material and related data must be compensated by appropriate procedures [6], [8], [21], [22], [25].

Thus, in Germany, involving independent competent ethics committees is necessary for both an assessment of human research biobanks themselves and (especially if legally required) an assessment of individual research projects making use of “broad consent” biological samples [28], [29]. Potential donors must be informed unmistakably about the broad scope of the intended use of his/her biological material and related data including the option of cross-border medical research [8], [19]. In this regard, we have learned much from previous population-based studies and disease-specific comprehensive national research networks, including their strategies for donor’s/study participant’s consent – and feedback management as well as stakeholder-oriented governance strategies, including access and sharing rules for human biological material and related data [10], [11], [12]. Experience gained from those previous and current nation-wide endeavors [15] strongly suggests that even under “broad consent” conditions a donor should be permitted to exclude certain research fields and/or procedures from the intended use of his/her biological material and related data, at least to some extent (similar but not identical to a so-called dynamic consent [30]).

In addition, donors must have the unconditional right to withdraw their consent and to have their biological material destroyed in that case.

Last but not least, human research biobanks are strongly recommended to reciprocate by making their implemented rules (governance/policies) and processes transparent and by fostering public involvement. Communicating concepts, objectives, results and future benefits of biobanks for both the respective donors and the general public is mandatory for human research biobanks in order to establish a trustful relationship with current and future donors [40], [41], [42], [43].