Sabina Gainotti

The TREAT‐NMD Duchenne Muscular Dystrophy Registries: Conception, Design, and Utilization by Industry and Academia

Duchenne muscular dystrophy (DMD) is an X‐linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT‐NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT‐NMD. For the DMD registries within TREAT‐NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT‐NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.

Improving the informed consent process in international collaborative rare disease research: effective consent for effective research

The increased international sharing of data in research consortia and the introduction of new technologies for sequencing challenge the informed consent (IC) process, adding complexities that require coordination between research centres worldwide. Rare disease consortia present special challenges since available data and samples may be very limited. Thus, it is especially relevant to ensure the best use of available resources but at the same time protect patients’ right to integrity. To achieve this aim, there is an ethical duty to plan in advance the best possible consent procedure in order to address possible ethical and legal hurdles that could hamper research in the future. Therefore, it is especially important to identify key core elements (CEs) to be addressed in the IC documents for international collaborative research in two different situations: (1) new research collections (biobanks and registries) for which information documents can be created according to current guidelines and (2) established collections obtained without IC or with a previous consent that does not cover all CEs. We propose here a strategy to deal with consent in these situations. The principles have been applied and are in current practice within the RD-Connect consortia – a global research infrastructure funded by the European Commission Seventh Framework program but forward looking in terms of issues addressed. However, the principles established, the lessons learned and the implications for future research are of direct relevance to all internationally collaborative rare-disease projects.

The EPIRARE proposal of a set of indicators and common data elements for the European platform for rare disease registration

BackgroundThe European Union acknowledges the relevance of registries as key instruments for developing rare disease (RD) clinical research, improving patient care and health service (HS) planning and funded the EPIRARE project to improve standardization and data comparability among patient registries and to support new registries and data collections.MethodsA reference list of patient registry-based indicators has been prepared building on the work of previous EU projects and on the platform stakeholders’ information needs resulting from the EPIRARE surveys and consultations. The variables necessary to compute these indicators have been analysed for their scope and use and then organized in data domains.ResultsThe reference indicators span from disease surveillance, to socio-economic burden, HS monitoring, research and product development, policy equity and effectiveness. The variables necessary to compute these reference indicators have been selected and, with the exception of more sophisticated indicators for research and clinical care quality, they can be collected as data elements common (CDE) to all rare diseases. They have been organized in data domains characterized by their contents and main goal and a limited set of mandatory data elements has been defined, which allows case notification independently of the physician or the health service.ConclusionsThe definition of a set of CDE for the European platform for RD patient registration is the first step in the promotion of the use of common tools for the collection of comparable data. The proposed organization of the CDE contributes to the completeness of case ascertainment, with the possible involvement of patients and patient associations in the registration process.

‘You should at least ask’. The expectations, hopes and fears of rare disease patients on large-scale data and biomaterial sharing for genomics research

Within the myriad articles about participants’ opinions of genomics research, the views of a distinct group – people with a rare disease (RD) – are unknown. It is important to understand if their opinions differ from the general public by dint of having a rare disease and vulnerabilities inherent in this. Here we document RD patients’ attitudes to participation in genomics research, particularly around large-scale, international data and biosample sharing. This work is unique in exploring the views of people with a range of rare disorders from many different countries. The authors work within an international, multidisciplinary consortium, RD-Connect, which has developed an integrated platform connecting databases, registries, biobanks and clinical bioinformatics for RD research. Focus groups were conducted with 52 RD patients from 16 countries. Using a scenario-based approach, participants were encouraged to raise topics relevant to their own experiences, rather than these being determined by the researcher. Issues include wide data sharing, and consent for new uses of historic samples and for children. Focus group members are positively disposed towards research and towards allowing data and biosamples to be shared internationally. Expressions of trust and attitudes to risk are often affected by the nature of the RD which they have experience of, as well as regulatory and cultural practices in their home country. Participants are concerned about data security and misuse. There is an acute recognition of the vulnerability inherent in having a RD and the possibility that open knowledge of this could lead to discrimination.

Insurance Policies for Clinical Trials in the United States and in some European Countries

In clinical research there are important moral arguments supporting the need to offer a compensation to the injured research participants. Bene fi cence justi fi es compensation at least for the expenses of “reparative” health care, while justice requires that the risks of research do not fall exclusively on the research participants. Although the ethical arguments for compensating injured participants are generally acknowledged, the practical details are complicated — particularly the determination of the extent and duration of coverage and the assignment of responsibility for paying compensation.In this paper we analyze how several national legislations, in the United States and Europe deal with the following problems: the voluntary or compulsory requirement to draw up an insurance for the research participants; the kind of compensable injuries including death, serious harm, pain, suffering and economic losses; the compensability of harms which are inevitable in a trial and of health problems which can depend on a subject’s noncompliance or on the natural progression of the subject’s disease; the importance of the informed consent document and the details to be given to the research participants; the rules for compensation in phase 1 and phase 2 trials and in phase 3 and phase 4 trials, or the distinction among trials involving different levels of risk; the possibility to provide a no-fault compensation to the injured research participants when negligence cannot be established; the rules on insurance and compensation in public and private research; the actors responsible to provide compensation to the injured subjects (the State, private insurances, or both); the availability of temporal indications for the compensation of research participants.The comparative analysis highlights the strengths and weaknesses of the analyzed legislations and proposes a model for the insurance and compensation of the injured research participants, which hopefully promotes the principles of bene fi cence, autonomy and justice in research.

EPIRARE survey on activities and needs of rare disease registries in the European Union.

The EPIRARE project[1] aims to build consensus and synergies for the development of an EU platform for rare disease registries and to address relevant regulatory, ethical and technical issues associated with the registration of rare disease patients. To this aim, a survey was carried out among existing rare disease registries and databases to get information on their objectives, needs, governance mechanisms, sustainability, and measures for the compliance with regulatory and ethical requirements and for quality assurance, as well as expectations from and opinions on a registry platform. Responses were received from 255 registries, of which 220 active registries were selected based on the completeness of the response. Among responding registries, 18, 61, 17 and 3% were international, national, regional or local. The fraction of registries population based, hospital based and following case series or cohorts was, respectively 56, 23 and 20%. Epidemiological and clinical researches were the most declared scopes (respectively 71, 61% in a multiple answer question) and characterized two clearly different clusters of registries. Treatment efficacy and safety was the scope indicated by 45% registries. A wide heterogeneity is found regarding the disease coding system used, with 62% using their own or no code. Twenty-seven percent registries are established by law or to comply with regulatory requirements, while 73% as part of research projects or as an autonomous decision of clinicians or patients. Half of the registries shares data with other registries and 33% with centres of expertise, while 30% do not exchange with neither of them or with bio banks. Registries were established with no initial funding (21%) or with funding by public authorities (37%), industries and foundations (21%), research institutes and hospitals (25%), patients associations (16%) and the European Commission (15%). After the initial phase, more registries (25%) are run without specific funding; frequency of funding sources remains stable but for the European Commission, which decreases to 6%. Different procedures are applied for quality assessment, but each of them is applied by 46-58% registries. A main governing body is not present in 34% registries and 48% registries have no policy to ensure long-term sustainability. Main needs expressed are financial support, improved communication strategies and more extended geographical coverage, data sources and registry networking. The vast majority of respondents (80%) is favourable to a platform for registries and 60% doubts that new legislation can facilitate registration. Popularly expected platform services are technological tools, specific expert advice and resources.

ETHICAL MODELS UNDERPINNING RESPONSES TO THREATS TO PUBLIC HEALTH: A COMPARISON OF APPROACHES TO COMMUNICABLE DISEASE CONTROL IN EUROPE

Increases in international travel and migratory flows have enabled infectious diseases to emerge and spread more rapidly than ever before. Hence, it is increasingly easy for local infectious diseases to become global infectious diseases (GIDs). National governments must be able to react quickly and effectively to GIDs, whether naturally occurring or intentionally instigated by bioterrorism. According to the World Health Organisation, global partnerships are necessary to gather the most up-to-date information and to mobilize resources to tackle GIDs when necessary. Communicable disease control also depends upon national public health laws and policies. The containment of an infectious disease typically involves detection, notification, quarantine and isolation of actual or suspected cases; the protection and monitoring of those not infected; and possibly even treatment. Some measures are clearly contentious and raise conflicts between individual and societal interests. In Europe national policies against infectious diseases are very heterogeneous. Some countries have a more communitarian approach to public health ethics, in which the interests of individual and society are more closely intertwined and interdependent, while others take a more liberal approach and give priority to individual freedoms in communicable disease control. This paper provides an overview of the different policies around communicable disease control that exist across a select number of countries across Europe. It then proposes ethical arguments to be considered in the making of public health laws, mostly concerning their effectiveness for public health protection.

How Legislation on Decisional Capacity Can Negatively Affect the Feasibility of Clinical Trials in Patients with Dementia

Antipsychotic drugs are widely used to treat behavioural and psychological disturbances associated with Alzheimers disease (AD), although only modest evidence from randomized controlled trials supports their efficacy, and increasing evidence from post-marketing surveillance shows serious adverse events associated with their use, including increased mortality. The AdCare study, a non-profit, randomized, placebo-controlled, double-blind, multicentre, pragmatic trial coordinated by the Italian National Institute of Health, aimed to evaluate the long-term safety and efficacy profiles of three atypical antipsychotic drugs (risperidone, olanzapine and quetiapine) and one conventional antipsychotic drug (haloperidol) in treating psychosis, aggression and agitation in outpatients with AD. The study was planned to be carried out in 19 clinical centres and to enrol 1000 outpatients. According to Italian law, in the case where a patient is considered unable to give informed consent, a legal representative designated by the court has to provide it. Because of difficulties in the informed consent procedure, the study had to be prematurely interrupted. From February 2009 to April 2010, 83 patients gave informed consent to participate in the trial. Fifty-six patients (68%) were included with consent given by a legal representative, while 27 patients (32%) were considered to provide personal informed consent on the basis of the results from a specifically built procedure. Patients and caregivers were offered the opportunity to participate in the trial before the occurrence of behavioural disturbances, in order to provide them with enough time to consider their participation in the study. Twenty-three patients experienced behavioural, clinically relevant symptoms and were randomized to the study drug; all randomized patients except one had consent for inclusion in the study given by legal representatives. After trial interruption, all patients taking an active drug continued treatment with the same molecule in clinical practice. Randomized controlled trials are acknowledged as the gold standard source of evidence on drug safety and efficacy. The AdCare study showed that an excessively rigid regulation can become a major obstacle while carrying out therapeutic research with incapacitated persons.

The Quality of Rare Disease Registries: Evaluation and Characterization

Background: The focus on the quality of the procedures for data collection, storing, and analysis in the definition and implementation of a rare disease registry (RDR) is the basis for developing a valid and long-term sustainable tool. The aim of this study was to provide useful information for characterizing a quality profile for RDRs using an analytical approach applied to RDRs participating in the European Platform for Rare Disease Registries 2011-2014 (EPIRARE) survey. Methods: An indicator of quality was defined by choosing a small set of quality-related variables derived from the survey. The random forest method was used to identify the variables best defining a quality profile for RDRs. Fishers exact test was employed to assess the association with the indicator of quality, and the Cochran-Armitage test was used to check the presence of a linear trend along different levels of quality. Results: The set of variables found to characterize high-quality RDRs focused on ethical and legal issues, governance, communication of activities and results, established procedures to regulate access to data and security, and established plans to ensure long-term sustainability. Conclusions: The quality of RDRs is usually associated with a good oversight and governance mechanism and with durable funding. The results suggest that RDRs would benefit from support in management, information technology, epidemiology, and statistics.

Overview of existing initiatives to develop and improve access and data sharing in rare disease registries and biobanks worldwide

ABSTRACT Introduction: There are currently several strategies developed to facilitate access and data sharing in the rare disease field. These strategies have paid special attention to the importance of rare disease patient registries and biobanks, as they are essential tools for surveillance and the provision of biosamples and phenotypic and genetic data for research worldwide. However, they are usually fragmented by disease, data model and country. Moreover, these resources have restricted access in order to protect privacy of patient data. Areas covered: This article is an overview of existing initiatives that facilitate access to rare disease patient registries and biobanks, future challenges of accessing data/biosamples and the major barriers to achieve interoperability and worldwide sharing. Expert opinion: RD patient registries and biobanks play an important role in the discovery of either new rare diseases or new phenotype-genotype correlations. However, there is still little access to data and important limitations regarding interoperability between these resources. The improvement of access and data sharing among patient registries and biobanks worldwide, together with the establishment of harmonized regulatory criteria, might enhance knowledge on rare diseases and the discovery of new diagnostic and therapeutic procedures.