Ethical issues of the RBDD project

Human experimentation will be limited to primary cells and cell lines obtained from patients provided by collaborating groups.
Informed consent will be obtained according to the recommendations of the Institutional Ethical Committees. The primary ethical, legal, social and safety issues raised by this project are:

I.	The ethical and legal issues involved in collecting biological samples from patients affected by rare bleeding disorders (RBDs);
II.	The ethical and legal issues involved in linking clinical data with genetic information from patients;
III.	The ethical and social implications of the results of this research.

 

The rare bleeding disorders database (RBDD) project will be operated to the highest ethical standards, and with careful attention to best practice in research governance. Due regard will be paid to the relevant national and international standards, including the World Medical Association's 'Declaration of Helsinki', the Council of Europe's 'Convention on Human Rights and Biomedicine', and UNESCO's 'Universal Declaration on the Human Genome and Human Rights'. The RBDD, published at www.RBDD.org, established with the aim of collecting clinical, genetic and treatment data from patients affected by RBDs, has already been approved by the Ethical Review Board of the IRCCS Foundation, Maggiore Hospital, Mangiagalli and Regina Elena, University of Milan. The IRCCS Foundation, Maggiore Hospital, Mangiagalli and Regina Elena Ethics Committee will be responsible for compliance with all appropriate national and international ethical standards and for ensuring that appropriate principles, policies and practices are adopted in the preparation of accounts.

Ethics and the use of DNA, serum, plasma and platelet samples
The database will be used to collect information on DNA and plasma samples derived from as many patients affected by RBDs as possible. Informed consent was obtained from all the already recruited patients. When a new sample is to be collected for inclusion in the project, the patient will be informed of the purpose of the project and invited to participate. The information provided before asking for the informed consent of patients/donors will reflect the aims and objectives of the project. A 10 ml sample of citrated blood will be collected from each subject who agrees to participate. This sample will be used to obtain plasma, for the screening coagulation laboratory assays and more specific and advanced diagnostic tests (phenotype characterisation), and cells in order to extract DNA for genetic analysis. Consent to the use or collection of blood will be requested after having described the principal aims of the RBDD, one of which is the adhesion to research studies designed to increase the understanding of the basis of RBDs. The subject will also be informed of how a blood sample may be used in the project (collection of genetic information, transfer of samples between partner sites, sequencing, linkage with proteomic and other biological information and, when relevant, linkage to clinical information). Finally, it will be clearly explained that consent to participation in the project can be withdrawn at any time and in this case the subject can ask for elimination of all his or her biological samples . Clinical information will be extracted in non-identifying forms. In cases that data are shared or circulated among collaborators (an essential feature of this collaboration), it will be in coded form to prevent direct linkage to personally identifying information. 'Breaking the code' to re-identify individuals will only be permitted under exceptional circumstances, with the prior approval of a competent ethics committee. In cases that data are transmitted outside the collaboration, this will be done in compliance with the norms of EU data protection law. Prospective consent to future, as yet undefined, usage is currently a controversial topic in bioethical literature, but most commentators agree that samples will be collected only for uses which are consistent with the originally intended research (in this case, research into the diagnostics, therapeutics, genetics and proteomics of RBDs) as a sufficient safeguard for patients' interests, without posing an unduly restrictive requirement on future use of this valuable resource.

The ethical and legal issues involved in linking identifiable patient information to genetic information As noted above, there are issues of confidentiality and data protection involved in the extraction and linkage of any identifying clinical information, which will be managed through the informed consent of the patient and appropriate systems of information governance. In the case of genetics, the information to be collected in this project should result in the identification of genetic causes of RBDs. This information will be given to the samples' donors through a medical report signed by the person responsible at the Centre where the genetic diagnosis is made. Information on the general aims and achievements of the RBDD programme will be made publicly available.

Research involving persons (individuals or populations), outside the EU community
The RBDD project provides the opportunity to enrol a large group of patients affected by RBDs, most of whom will probably come from outside the EU community. The form for requesting informed consent will be sent to all Clinical Centres joining the RBDD project. Each Centre can send clinical data and biological samples from patients and relatives after certification by the main clinician that all subjects have signed our informed consent form or an analogous one, specific for the Country of origin and in accordance with national and international legislation. It is possible that there will be children among the recruited patients and relatives; in these cases, the child's parents or guardians will be asked to consent to the child's participation in the project.

The social and ethical implications of the results
The RBDD project offers clear prospects for the understanding of the molecular causes of RBDD. It will provide diagnostic tools and foster therapies for the management of these diseases. RBDs are more prevalent in developing countries, where the practice of consanguineous marriage is diffuse. The knowledge of all the molecules involved in these disorders will make prenatal diagnosis possible in at-risk kindred of affected individuals and will promote novel therapeutic approaches to anticoagulation.

Conflict of Interest
The partners involved in the RBDD project have no conflict of interest.