The Ariane-IPF ERS Clinical Research Collaboration: seeking collaboration through launch of a federation of European registries on idiopathic pulmonary fibrosis

Rationale for a multinational registry

Idiopathic pulmonary fibrosis (IPF) is the most prevalent of rare pulmonary diseases [1], and the most severe of the chronic forms of idiopathic interstitial pneumonias, with rising incidence and prevalence [2–4]. The prognosis for people diagnosed with IPF is a median survival of 3–3.5 years [1].

With a consensus international definition for IPF, and the approval of pirfenidone and nintedanib worldwide, the landscape of research and pharmacological studies has evolved dramatically. Numerous compounds are in the research pipeline and hopefully novel drugs will soon be approved for IPF. Not only have clinical trials assessed the efficacy, safety and tolerability of the drugs, they also have provided invaluable knowledge about disease course, including rates of progression, acute exacerbations, predictors of prognosis and non-elective hospitalisation [5], as well as new insights about comorbidities including gastro-oesophageal reflux and the potential effect of concomitant medications [6–9], thereby often generating new hypotheses.

However, data obtained from clinical trials are restricted by selection bias in many ways, in IPF as in other fields [10–12]. Eligibility criteria of large clinical trials aim at recruiting patients with a relatively recent diagnosis, few comorbidities and possibly mild impairment of pulmonary function, and tend to select individuals who are younger, are in better general condition, and have less impaired health-related quality of life and disease severity than the average patient seen in the clinic [13, 14]. Results from post hoc analyses evaluating the effect of co-medications or comorbidities in the patient population of large trials may therefore also be influenced by selection bias, even if performed in those randomised to placebo.

The added value of registry data in IPF has been emphasised previously, including in the European Respiratory Journal [15]. In IPF, registries have provided useful information on disease course in a broad population of patients diagnosed and treated in the community throughout the world. To take a few selected examples, data from the German INSIGHTS-IPF (Investigating Significant Health Trends in Idiopathic Pulmonary Fibrosis) registry have described the impact on quality of life of living with IPF [16], encompassing all patients diagnosed with IPF and followed for a prolonged follow-up time, as a complement to clinical trials, which are limited to eligible subjects and more limited in time [13]. Data from the eurIPFreg registry (European IPF Registry) have showed the evolving practice regarding lung biopsy and the emerging use of transbronchial cryobiopsy in Europe [17]. Data from the Australian IPF Registry have described the outcome of patients with a “working diagnosis of IPF” (e.g. patients whose disease presentation was sufficiently similar to IPF but who did not strictly fulfil IPF diagnostic criteria), and showed it to be comparable to that of patients with a more definite diagnosis of IPF [18], an issue which would be difficult to address outside of prospective registries. Data from the Australian IPF Registry also showed that patients receiving antifibrotic medications had better survival than those not on antifibrotic medications, independent of underlying disease severity, confirming meta-analysis of trials [19], an observation further supported by the eurIPFreg registry [17]. The Czech EMPIRE registry (European MultiPartner IPF Registry) has showed the sustained effect of pirfenidone at 2 years [20]. Importantly, these data complement those from clinical trials. At the most recent international congress of the European Respiratory Society (ERS) in Paris, France (September 2018), an entire session was dedicated to data emanating from registries throughout Europe, illustrating the exponential research in this field. An IPF registry has also been created in the USA under the auspices of the Pulmonary Fibrosis Foundation, with more than 2000 patients included to date, which undoubtedly will provide novel insights.

There remain, however, limitations to the scope of analysis that can be performed in individual registries. Due to the large number of cases needed to perform subgroup analysis and propensity score analysis, and the risk of missing data in registries, even larger datasets than those collected thus far are warranted. For example, there are a number of unmet medical and patient needs regarding the natural course of the disease, including the rate and outcome of acute exacerbations of IPF, the tolerance, safety and efficacy of available drugs in real-life settings, the patterns of care and heterogeneity of cases across Europe, comorbidities, genetic determinants of susceptibility to the disease and predictors of disease outcome and treatment response, etc. International datasets and large cohort size also give way to benchmarking by country or region, or by time periods [17]. Indeed, the power of federated registries has been demonstrated in other rare diseases, especially cystic fibrosis [21].

Ariane-IPF: a future European federated registry

Because IPF is a rare disease, we need to join forces to address the challenges of research in this field [22]. To address the need for large datasets, a unified multinational registry for IPF has been warranted for years [23, 24] but has yet to be created. Recently, similar to other Clinical Research Collaboration (CRC) programmes [25], the ERS, with the support of Assembly 12 on interstitial lung diseases, has launched a CRC in IPF entitled Ariane-IPF, to design and create a pan-European meta-registry/federated registry of IPF. Ariane-IPF, currently at the stage of being designed and seeking funding, aims at providing a platform that allows the meta-analysis of existing registries, and bringing together healthcare providers, researchers, industry and patients with the aim of advancing transnational research collaboration and improving the quality of life and treatment options for people living with IPF. The tool will be instrumental for observing the course of the disease (phenotypes), understanding variations in outcome across geographically diverse populations, describing case patterns, assessing effectiveness of interventions, and monitoring safety and harm. Initiated with clinical data, Ariane-IPF may further pave the way for a virtual meta-biobank. In addition, data in the federated registry will be findable and accessible to researchers by being integrated with the new European Rare Disease Registry Infrastructure platform (https://eu-rd-platform.jrc.ec.europa.eu).

Since the initiation of the Ariane-IPF project, the proposal of a meta-registry in Europe has been well received by the IPF community, and the scientific committee for Ariane-IPF has met and includes representatives of all large existing registries in Europe, as well as ERS, European Reference Network (ERN) and European Lung Foundation representatives. ERS members were surveyed in 2017 (table 1), identifying no fewer than 93 individual registries and biobanks for interstitial lung diseases and especially IPF within Europe. Existing registries are highly heterogeneous in goals, size, exhaustivity, quality control, scientific analysis, publication and funding, so that data will need to be harmonised before entering Ariane-IPF. The survey further demonstrated interest of respondents to participating in a registry.

A priority project for Ariane-IPF has been identified, which will start with the integration of the main active and mature IPF registries in Europe. Examples of shortlisted registries include INSIGHTS-IPF (Germany), EXCITING-ILD (Germany), RaDiCo-ILD (Rare Disease Cohort; France), PROOF Registry (Belgium/Luxembourg), Swiss IIP Registry, Dutch national IPF registry, Spanish EPAR registry, National Swedish Registry, INDULGE IPF (Greece), etc. It is anticipated that all main registries within Europe will eventually join the forces of the Ariane-IPF registry while it grows and matures. It is further considered that countries or individual clinicians not yet participating in any IPF registry will be able to directly contribute data to the Ariane-IPF integrated platform.

Structure and organisation of Ariane-IPF

Whereas momentum and enthusiasm have been generated, the Ariane-IPF platform for the federation of participating existing registries has yet to be funded and created. The purpose of this editorial is to foster the momentum, to share the vision, to invite collaboration and to call for funding.

As shown in figure 1, the proposed Ariane-IPF platform will be composed of “model” registries, which will be provided to countries that do not have an independently sustainable registry. The model registry will be based on the “best” of the current IPF registries and will be extendable to meet unique national and study needs. The model registry will automatically share pseudonymised data with the federated registry and the real-world data platform. Sustainable and well-established registries from larger countries could transfer longitudinal data annually to the federated registry through pseudonymised assessments.

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FIGURE 1

General proposed architecture of the Ariane-IPF integrated platform. Model national registries (green) will be interoperable and linked to the federated registry (blue) and the real-world data study platform (red). Patients may contribute data through patient portals (green). Independent registries (yellow) could transfer longitudinal data annually to the federated registry. Multiple pharmaceutical partners will be able to fund multiple proprietary contract research organisation (CRO)-managed real-world data studies (red) from cohorts of model national registry patients.

Several aspects underpinning the creation of Ariane-IPF must be emphasised. First of all, participating in Ariane-IPF will be based on the willingness of individual registries to share an agreed minimum dataset of static and longitudinal data. This will require an agreement to be settled between the Ariane-IPF platform and the respective scientific committees of participating registries. Data will remain proprietary of the individual registries, which will be able to continue data analysis and publication of their own data. Participating in the Ariane-IPF must be seen as a new opportunity to participate in a broader set of data and upscaled analysis in a collaborative initiative, on top of (and not instead of) existing efforts. Ariane-IPF will generate annual benchmarking reports, which will foster involvement of stakeholders.

Next, the Ariane-IPF platform will be developed in close collaboration with the European Lung Foundation and patient group consortium, especially the European IPF Federation. It is considered that it may incorporate input directly from the patients, thereby contributing to the development of patient-reported outcomes.

Collaboration and partnership with the pharmaceutical industry is another crucial aspect of Ariane-IPF. The integrated real-world data platform will guarantee future funding and sustainability of the solution for the IPF community, and will provide verifiable longitudinal data necessary for pharmaceutical industry-funded studies. Access to the data will have to be pre-approved by the Ariane-IPF scientific committee, have the consent of the patients, and have the agreement of the steering committee of the individual registries. We envision Ariane-IPF as the preferred tool to obtain reliable real-world evidence necessary to support drug development, in addition to becoming an invaluable tool for academic research in IPF.

Future and challenges

Many challenges are still to be faced by Ariane-IPF. Standardisation and harmonisation of data across datasets is a challenging yet essential process to enable individual-level pooling of data. An integrated database will be developed to provide high-quality data. Legal, regulatory and ethical aspects need to be considered on a case-by-case basis for each registry. Funding and economic models need to be ascertained. Most importantly, formal agreement must be obtained from the steering and scientific committees of individual registries that have already agreed in principle to participate and share data. Maximum attention has been and will be paid to information from colleagues, authorship lists and acknowledging the intellectual contributions of everyone. Colleagues must be reassured that data sharing will respect every aspect of the patients' and the doctors' agreement, while the intellectual contribution of everyone needs to be acknowledged.

The huge dataset generated by combining several registries will allow investigation of a wide range of clinically relevant questions through real-world pragmatic studies. Ariane-IPF can be the backbone of many research initiatives. The scientific committee of Ariane-IPF will consider any research idea from academic colleagues as well as questions raised by industry partners. For example, Ariane-IPF can help in identifying patients and sites for clinical trials as in a virtual clinical trials network, and can help in identifying relevant clinical outcomes. Further to the clinical integrated platform, Ariane-IPF has the ambition to set the stage for a virtual meta-biobank, which would require the collaboration of many stakeholders, especially the ERN for respiratory disease, ERN-LUNG. Indeed, virtual meta-biobanks constitute an essential resource for translational research, especially understanding the interactions between genetic and epigenetic risk factors and environmental exposures that lead to disease development.

Conclusion

Just like the Ariane rocket, which has been launching satellites around the globe since 1979, following an ambitious collaborative programme initiated by the European Space Agency, Ariane-IPF is expected to generate scientific progress and publications, as well as further development and research activities. Further to academic studies and partnership with the pharmaceutical industry, the collaborative network enhanced by Ariane-IPF might create an alliance against pulmonary fibrosis, facilitate innovative trials, and allow future studies on fibrotic diseases beyond IPF [26–28]. Until Ariane-IPF is actually launched, we call all ERS members to contribute to their national IPF registry, and to support its participation in the Ariane-IPF initiative.