Over the last decade, rare disease research has seen tremendous developments in diagnostic efficiency and therapeutic interventions [1]. Contributing factors include the discovery of novel genes with new sequencing technologies, global collaborative efforts and commitments, and improved data and resource sharing. Adding to this are the growing number of genotype-phenotype datasets and matchmaking platforms, along with the trend towards patient-centered research, whereby patient organizations play a leading role in data generation and research recruitment. To maximize the impact of these initiatives in contributing substantive amounts of quality data for research use, practical model consent clauses are essential to enhance data interoperability as well as to meet the informational needs of participants, ensure proper ethical and legal use of data sources and participants’ overall protection.
To address this need, the International Rare Diseases Research Consortium (IRDiRC) and the Global Alliance for Genomics and Health (GA4GH) met to develop model consent clauses for rare disease research. The following proposed consent clauses are guided by the Framework for Responsible Sharing of Genomics and Health-Related Data [2] and other international and national ethics and legal consent frameworks. They provide the foundation for the harmonization and standardization of participant recruitment and consent processes for rare disease research. Although not all the proposed clauses are exclusive to the rare disease context, certain clauses are of particular importance to consent procedures for rare disease research and complement existing core elements found in “classical” or “generic” consent forms. It is hoped that together these clauses will ensure that research involving patients with rare conditions be deployed effectively to promote and catalyze collaborative multinational studies through interoperable and responsible research practices endorsed by IRDiRC and GA4GH.
Consent issues in rare disease research
Obtaining informed consent from research participants not only respects personal autonomy, self-determination, and the right to privacy but also seeks to prevent undue harm [3,4,5]. Research participants must be well informed of the research goals, benefits and risks, and the possibility to refuse participation and withdraw from research at any time without affecting their medical care. The voluntary expression of consent is fundamental to ethical research practices. In the rare disease research context, however, consent processes have become complex in the current landscape of technological and genomic advances, along with the extensive collection, pooling and dissemination of data worldwide. Because of the scarcity of patients and the need to share information internationally to find similar cases, data sharing and ‘matchmaking’ is imperative for rare disease research. Since most rare diseases appear in childhood, the recruitment of children and unaffected family members might further complicate consent processes [6]. Particular phenotypes of rare disease patients also often require the collection and sharing of audiovisual data (e.g., facial images, videos, etc.), the use of machine learning procedures for data phenotyping [7], and the bridging between clinical care and research [8] in this scientific domain.
Notably, the challenge in establishing consent policies for rare disease research stems from the dichotomy between the push for free-flow of data against concerns about loss of privacy. Patients with rare diseases often expect that data are shared for scientific advances in genomic medicine and rare diseases research. At the same time, patients are concerned about being identified, a risk inherent to data sharing [9] and enhanced in the rare disease context. Particularly, the likelihood of individual re-identification from genomic data, whether coded or anonymized, has been documented [10, 11], especially when such data has been linked with other sensitive familial, sociodemographic or audiovisual information. This is why international policy approaches to assess privacy risks in genomic research widely adopt as a criterion the “reasonable likelihood test” (i.e., based on the proportionate evaluation of real risks and benefits and the balance of probabilities, the possible benefits for participants must surpass potential consequences for their privacy) [12].
The singularity and diversity of rare diseases, combined with the small number of patients for each disorder, effectively precludes conventional research discovery approaches, including those directed at addressing privacy risks and concerns. Some rare disease research mandates cross-matching data between different centers for discovery and diagnostic purposes. Thus, absolute privacy protection is unrealistic in this realm. Coding and security tools serve to mitigate and protect against privacy risks. However, re-identification is often desired by patients for the return of results and so precludes anonymization [7, 13].
Hence, research involving rare disease participants is challenged by unique realities and overall impediments to genomic research, and thus, should be acknowledged in ethical and legal deliberations regarding research protocols, privacy protections, and consent standards. Rare disease participants are often well informed about their disease, highly motivated to participate in different research studies, and strong advocates for greater access to research. They may view identifiability risks as minor when weighed against the opportunity to gain a diagnosis or to support research advancements towards new therapies. Consequently, privacy interpretations should be broadened to include not only the right to confidentiality, secrecy and non-interference but also the positive right to “determine and manage personal information, and to actively have a say in one’s own private sphere” [14] and to realize the human right of everyone to “share in scientific advancements and its benefits [15, 16].” Moreover, privacy protections should go beyond rare disease participants to also protect and further the interests of their family members in familial and trio genomic studies [17].
As such, the adoption of governance frameworks, security measures, and standards (i.e., data management/access policies, Privacy Preserving Record Linkage [18] or unique identifying systems) has become the nexus from which privacy discourse has shifted [19]. Adding to this is a move towards a nuanced approach to consent standards that account for the unique complexities and specificities of rare disease research [20]. By obtaining proper informed consent, proportionality between protecting the rights and interests of rare disease participants and promoting good research is achievable. In fact, qualitative studies show that knowledgeable rare disease patients understand the need for large-scale data sharing and expect their data to be distributed and reused but require, nonetheless, that they be informed of such activities in order to maintain a level of protection and control [21, 22].
