An innovative and collaborative partnership between patients with rare disease and industry-supported registries: the Global aHUS Registry

The problems of rare disease research

In the case of rare diseases, the development of effective treatment strategies can be hampered by a lack of knowledge of the condition. Issues include a lack of basic research on the natural history of the disease and difficulty in recruiting sufficient patients for effective clinical trials. Furthermore, the research that is performed may not answer the questions considered most important by patients [4]. Patient registries have been identified as tools to increase knowledge of the natural history of rare diseases, as well as providing a real-world setting in which clinical therapies, drug safety, and quality of care can be monitored [5]. Registries also provide a cohort of patients who may be suitable for enrolment into subsequent therapeutic trials. A global registry may also be the only way to collect sufficient data for robust statistical analyses. The active participation of patients will therefore lead to improved management of rare-diseases and patient outcomes [6].

Patient engagement in research can be interpreted in several ways, such as information sharing amongst rare disease groups and the use of patient-driven registries to facilitate data collection. However, such activities do not give patients input to the research process; for a successful registry, providing a voice for patients to help recruitment, encourage active participation and influence the research agenda is key. Although there may occasionally be reluctance on the part of patients and academics to engage in partnerships with industry, the significant effort and costs of a patient registry are best met through public/private partnership [7, 8]. Therefore enhancing communication and understanding between these groups is imperative.

Atypical haemolytic uraemic syndrome

Atypical haemolytic uraemic syndrome (aHUS) is a rare genetic, life-threatening, chronic disease of children and adults caused by unregulated activation of the alternative complement pathway leading to systemic thrombotic microangiopathy (TMA) [9, 10]. A complement abnormality is described in 50–60% of patients but identification is not required for diagnosis [9, 11, 12]. Presentation can initially be mild, with patients reporting fatigue and influenza-like symptoms, or sudden and severe. aHUS often manifests as nonimmune microangiopathic haemolytic anaemia, thrombocytopenia, and acute organ failure. Historically, patients with aHUS had a poor prognosis with high morbidity due to chronic kidney disease, frequent graft failure after renal transplantation and high mortality rates [11, 12]. Differential diagnosis is based on exclusion of TMA caused by Shiga toxin-producing Escherichia coli-induced HUS and thrombotic thrombocytopenic purpura [9]. Other causes of TMA including (but not limited to) disorders of metabolism, drug toxicity and malignant hypertension should also be excluded [13]. Eculizumab, an anti-human C5 monoclonal antibody, is nowadays recommended for the treatment of aHUS following successful clinical trials in paediatric and adult patients with aHUS [14–16].

The Global aHUS Registry

The Global aHUS Registry (US National Institutes of Health www.ClinicalTrials.gov Identifier NCT01522183) is an observational, non-interventional, multicentre registry of patients with aHUS, and is a product of a partnership between worldwide academia, patients with aHUS and Alexion Pharmaceuticals, Inc. The aims of the Registry are to assess the long-term patient outcomes, and collect and evaluate safety and effectiveness data specific to the use of eculizumab, fulfilling post-marketing regulatory requirements. The Global Registry is open to patients of all ages with a clinical diagnosis of aHUS; an identified complement gene mutation or factor H autoantibody is not required. Patients with secondary aHUS are eligible and physicians can record the potential precipitating cause. Patient data are collected following a research protocol and in accordance with International Conference on Harmonisation Good Clinical Practice Guidelines and the Declaration of Helsinki. Clinical and patient reported data (e.g. a fatigue score completed by the patient) are collected at study enrolment and every 6 months thereafter. The methodology of the aHUS Registry and characteristics of the first 516 patients enrolled (from 16 countries) have recently been published [17]. Amongst this patient cohort, 60% had received plasma therapy, 60% had a history of dialysis, and in 20% one or more kidney transplants had been performed. Overall, 59% of patients had received eculizumab.

Scientific oversight, governance and coordination of the Global aHUS Registry are provided by an independent scientific advisory board (SAB). The SAB includes members with expertise in key specialties related to management of aHUS (e.g. adult and paediatric nephrologists, haematologists, and/or transplant nephrologists/surgeons) as well as representation from Alexion Pharmaceuticals. Also, as a result of the engagement process described here, a patient representative is now included on the SAB. Data collected by the Global aHUS Registry are accessible to participating and nonparticipating physicians who may request data access or specific analyses by submitting a concept sheet via the aHUS Registry website (http://www.ahusregistry.com/) for evaluation by the SAB.

Here, we describe the feasibility of a new model of collaboration between an international group of patient organisations with a rare disease and an industry-supported disease registry, as a way to promote patient-centred research.

The Global Registry SAB

In order to improve registry management transparency and data analysis, the Global aHUS Registry SAB members discussed methods to promote patient benefit from participation and disease information sharing. Thus, in May 2014, the SAB members resolved to invite a representative from a patient organisation to join the SAB with the objective of strengthening the collaboration between academic experts and patient organisations in order to further understand patients’ needs and how the aHUS Registry could help address them. The relationships between the stakeholders involved in the Global Registry are shown in Fig. 1.

The aHUS Alliance

In January 2013, representatives of patient organisations from six European countries advocating on behalf of aHUS patients met and agreed to collaborate as the aHUS Alliance (from Belgium, France, Italy, Russia, Spain and UK). Since then a further 6 organisations have become affiliated to the aHUS Alliance (from Australia, Canada, Germany, India, Netherlands and USA; http://www.ahusallianceaction.org/patient-associations/). One of the Alliance’s aims, listed in the inaugural “Declaration of Collaborative Aspirations”, was to work with international clinical aHUS research networks. In order to identify and prioritise areas of interest, the aHUS Alliance devised a questionnaire to conduct a global survey of patients with aHUS in 2014. The survey was available in English, French, Spanish, German, Italian and Dutch, and contained 28 questions seeking details of basic patient characteristics plus feedback on six issues commonly raised by patients with rare diseases; diagnosis, treatment, expert centres, research, registries and availability of information [18]. A similar survey was conducted in 2016, updated to include 46 questions [19]. The survey was promoted via social media and available on the Rare Connect and, in 2016, the aHUS Alliance websites.

To fulfil the aim of informing the SAB of research areas patients with aHUS considered the most important, the subject was included on the agenda for the third meeting of the aHUS Alliance in June 2015. Members were reminded about the call for research ideas to be brought to the meeting.

The session was facilitated by the Alliance’s aHUS registry representative. Initially there was a reluctance by the 22 representatives to respond, with an apprehension about articulating ideas in a way suitable for academics, disbelief that patient opinions would be considered seriously, and an unwillingness to give ideas to a commercial organisation for their perceived gain. To encourage contributions, it was highlighted that the Alliance would not critique, or assess in terms of the Registry data available, any proposals that were made.

A preliminary report was made available to all affiliates of the aHUS Alliance via an online file storage facility to allow other suggestions to be added. The final collated research suggestions were provided to the Chair of the aHUS Registry and reported to the SAB by the aHUS Alliance representative in November 2015 for consideration.

aHUS Alliance global surveys

Overall, responses were received from 214 patients or caregivers from 17 countries in 2014 and 233 respondents from 23 countries in 2016. Of those who responded, approximately a third reported they had participated in research (Fig. 2). In the 2016 survey, of the 96 responders who had not been involved in research, 85 (89%) said they would like to know how to participate.

In the 2014 and 2016 surveys, a similar proportion reported being involved in any patient registry (45% and 42%, respectively), and in 2016 only 1% of respondents did not wish to participate (Fig. 3). Around 30% of responders in both surveys did not know if they or the person with aHUS they cared for were enrolled in a registry. Overall, there was a trend with time towards a more active and positive patient role in research.

When asked what would encourage greater patient participation in research studies or clinical trials, three options were selected by approximately half of the respondents (Fig. 4). All the options, which covered receiving more information in one form or another, were selected by at least 30% of respondents.

Classification and prioritisation of patient research proposals

A paradigm shift for patient participation in disease-related research decision-making?

Patients with rare diseases have limited access to useful information to guide treatment decisions; providing patients with the opportunity to ask research questions may help to ensure that research efforts in rare diseases address relevant clinical questions and patient-centred health outcomes [20]. The active participation of patients and their representatives in research, whether a registry or clinical trial, can potentially lead to improvements in enrolment, data collection and quality, the credibility of results and their direct applicability to patients [24]. The inclusion of a patient representative on the Global aHUS Registry SAB will also improve the dissemination of outcomes to patients, thus increasing the transparency of the research process.

In order to promote changing the role of the patient in a registry from passive (patient is a data point) to active (patient is a researcher), [24] the participation of patients in the Global aHUS Registry is now actively supported by a patient representative working alongside the SAB. The patient advocate will assist in developing strategies to encourage voluntary patient participation in the Registry, will convey information from patients about their experience with the Registry, and will help the SAB share the results of the Registry with other patients.

A formal structure for partnerships between patient groups and clinical researchers

The Dialogue Model [25] has been identified as a construct for the continuing development of the partnership in the context of the Registry. The Model has six stages (exploration, consultation, prioritisation, integration, programming and implementation), of which the emerging partnership has reached the start of the third stage. Not completing the early stages fully and satisfactorily can be predictive of a failure to sustain progress to successful implementation.

Completion of a robust systematic evidence assessment review of the knowledge gap needs to be reviewed by the SAB as well as the Alliance, to arrive at an agreed list of specific patient research priorities, which then must be integrated with the Registry’s other research agendas from clinicians and industry. With an integrated list of research topics finalised, it will then be possible to move to a sequential programming of topics for direct study by the SAB, or indirectly, through encouragement of external investigators to use the Registry data for other priority topics.