Use of a rare disease patient registry in long-term post-authorisation drug studies: a model for collaboration with industry
Authors: Diana Bilton, Noreen Caine, Steve Cunningham, Nicholas J Simmonds, Rebecca Cosgriff, Siobhán B Carr
Journal: The Lancet Respiratory Medicine (2018)

When questions remain after assessment of novel therapeutics in phase 3 trials, licensing can be deferred while clarification is sought. Post-authorisation safety studies (PASS) and post-authorisation efficacy studies (PAES) have been introduced to help deliver new medicines to patients sooner. Regulators recognise the benefits of using patient registries to deliver these studies, and such use is encouraged by the European Medicines Agency (EMA).1European Medicines AgencyPatient Registries Initiative.http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000658.jspDate accessed: April 20, 2018Google Scholar Patient and disease registries are typically developed by the clinical community. While not usually designed for post-authorisation assessment of safety or effectiveness, registries can be adapted for this purpose, and have the benefit of providing longer term understanding of a specific disease. Treatment registries developed by pharmaceutical companies usually provide specific post-authorisation data limited to the timeframe of the request, leaving no legacy data for the wider community. The UK Cystic Fibrosis Registry (UKCFR), with records of over 10 000 patients, is sponsored by the UK Cystic Fibrosis Trust (UKCFT). With appropriate authorisations and consent, data representing 99% of UK patients with cystic fibrosis are entered by care teams in all UK cystic fibrosis centres.2Taylor-Robinson D Archangelidi O Carr S B et al.on behalf of the CF-EpinNet collaborationData resource profile: the UK Cystic Fibrosis Registry.Int J Epidemiol. 2017; 47: 9-10eCrossref Scopus (51) Google Scholar Data are collected from multiple disease domains (demographics, diagnosis, complications, mortality, laboratory data, nutrition, pulmonary function, respiratory microbiology, and physiotherapy) with a summary reported annually.3Cystic Fibrosis TrustUK CF Registry annual data report.www.cysticfibrosis.org.uk/registryreportsDate: 2016Date accessed: April 23, 2018Google Scholar In 2015, the UKCFR passed an audit against Good Pharmacoepidemiology Practice standards. The UKCFT pharmacovigilance programme began in 2012 and was initiated by EMA requests to three companies to develop long-term safety studies for cystic fibrosis products. The EMA produced guidelines and templates for PASS protocols and final reports in 20124European Medicines AgencyGuideline on good pharmacovigilance practices (GVP) module VIII—post authorisation safety studies 2012. EMA/813938/2011.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129137.pdfDate accessed: April 20, 2018Google Scholar and for PAES in 2015.5European Medicines AgencyScientific guidelines on post authorisation efficacy studies. EMA/PDCO/CAT/CMDh/PRAC/CHMP/261500/2015.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/12/WC500219040.pdfDate accessed: April 20, 2018Google Scholar Key considerations that affected the UKCFT's decision to support this initiative included the potential for improving the methodology of long-term safety studies and the opportunity for engaging and encouraging industry involvement in therapeutic products for cystic fibrosis. The principal components of the pharmacovigilance model are; a UK lead investigator, who is an adult or paediatric cystic fibrosis physician, to provide independent clinical guidance and registry expertise to industry partners and the EMA in the development of the study protocol, and to contribute to the interim and final reports; senior statisticians, independent of the marketing authorisation holder (MAH), to contribute to the development of the study protocol and statistical analysis plan, conduct analyses, and draft reports (EMA designated formats are adopted for reporting of summary anonymised data);6European Medicines AgencyPASS report guidelines.http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2013/01/WC500137939.pdfDate accessed: April 20, 2018Google Scholar pharmacovigilance programme support to produce delivery plans for interim and final study reports, from drafting to final version (approximately 2–3 months). The MAH submits reports to the EMA, sharing feedback with the UKCFR to enable any changes needed to the analysis for subsequent reports. The UKCFT has worked with an NHS research and development professional and legal advisers to develop a standard services agreement between the UKCFT and the MAH, the main provisions of which are shown in the panel.PanelStudy services agreement provisionsEngagementClear exposition of the services to be provided, in accordance with the study protocol.Study governanceParties comply with all applicable laws, statutes, and guidance of the European Union and the UK.ConfidentialityNon-disclosure of personal data and patient-level data in study reports; company and UK Cystic Fibrosis Trust (UKCFT) business confidentiality.Intellectual propertyThe UKCFT grants a licence to the company for access to anonymised data analysis and resulting reports only.Stated useSummary data reports to be used only for the agreed and stated purpose of a post-authorisation safety or efficacy study.PublicationProvisions to ensure that results of scientific interest are published in the public domain.FundingThe financial agreement between the UKCFT and the marketing authorisation holder ensures that the company covers all the costs of conducting the study and that none of the work is subsidised by either the Charity or the NHS. Each company pays a set-up fee to cover the costs incurred by the UKCFT in adding any new variables to the UK Cystic Fibrosis Registry, and the preparatory work needed to agree the study protocol and the service agreement. The services funded during the length of the study include a contribution to the costs of data collection within cystic fibrosis centres, provided in the form of grants from the UKCFT, and the full costs of project management, analysis, and reporting. Engagement Clear exposition of the services to be provided, in accordance with the study protocol. Study governance Parties comply with all applicable laws, statutes, and guidance of the European Union and the UK. Confidentiality Non-disclosure of personal data and patient-level data in study reports; company and UK Cystic Fibrosis Trust (UKCFT) business confidentiality. Intellectual property The UKCFT grants a licence to the company for access to anonymised data analysis and resulting reports only. Stated use Summary data reports to be used only for the agreed and stated purpose of a post-authorisation safety or efficacy study. Publication Provisions to ensure that results of scientific interest are published in the public domain. Funding The financial agreement between the UKCFT and the marketing authorisation holder ensures that the company covers all the costs of conducting the study and that none of the work is subsidised by either the Charity or the NHS. Each company pays a set-up fee to cover the costs incurred by the UKCFT in adding any new variables to the UK Cystic Fibrosis Registry, and the preparatory work needed to agree the study protocol and the service agreement. The services funded during the length of the study include a contribution to the costs of data collection within cystic fibrosis centres, provided in the form of grants from the UKCFT, and the full costs of project management, analysis, and reporting. Funding to support the pharmacovigilance programme has driven improvements in the registry and enabled a financial contribution to be made to UK cystic fibrosis centres to facilitate data entry. The subsequent enhancements to the UKCFR have been of benefit to other researchers using the registry, and to the NHS in monitoring the effect of new drugs. The most important element in study design is the ability to capture information on all users of the medicine in a real-world situation, which can include off-label use and patients with mild or severe disease who are often excluded in the randomised control trial setting. The ability to compare exposed and unexposed patients in cohorts matched for key characteristics is a great strength of patient registries, and predefined comparator groups (usually selected with a propensity scoring system) allow longitudinal tracking of outcomes. In the development of registry-based post-authorisation studies, the EMA recommends that they should themselves liaise more directly with disease registry holders, rather than via the MAH, at an early stage in the development of study protocols.7European Medicines AgencyReport on cystic fibrosis registries—workshop.http://www.ema.europa.eu/docs/en_GB/document_library/Report/2017/10/WC500236631.pdfDate: 14 June 2017Date accessed: April 20, 2018Google Scholar This recommendation is intended to improve clarity on what information is needed and what is available. The UKCFR endorses early engagement to avoid unrealistic expectations and to facilitate early implementation of any additional registry data fields. Improved communication should significantly shorten the current timeline of 12–18 months for agreeing study protocols, thus facilitating earlier study completion and reporting. The Life Sciences Industrial Strategy8Office for the Strategic Coordination of Health ResearchLife sciences industrial strategy—a report to the government from the life sciences sector. Office for the Strategic Coordination of Health Research, London2017Google Scholar urges the development of more national patient registries, particularly in rare or orphan diseases, actively supported by patient charities. The UK Government has agreed to the implementation of the UK Strategy for Rare Diseases,9Department of HealthThe UK strategy for rare diseases. Department of Health, London2013Google Scholar which calls for better use of rare disease registries in research and development. The UKCFR has developed a successful model for partnership with industry to conduct long-term safety and efficacy studies, aimed at improving the safety of medicines and the quality of pharmacovigilance that can hopefully be modified for use in other rare diseases. We thank people with cystic fibrosis and UK cystic fibrosis centre directors, for continuing to support the UKCFR; the staff who enter data into the UKCFR; and Patricia McGettigan, Clinical Pharmacologist and Lead for the Patient Registries Intitiative at the Pharmacovigilance and Epidemiology Department of the EMA, for review of the manuscript. RC reports fees to her employer (the UKCFT) from pharmaceutical companies involved in the UKCFT Pharmacovigilance Programme (Pharmaxis, Vertex, Teva, and Chiesi), during the conduct of the study. NJS reports personal fees from Raptor, Chiesi, Vertex, Teva, Roche, Novartis, Pharmaxis, PTC Therapeutics Inc, and Pulmocide, outside of the submitted work. SBC reports personal fees and non-financial support from Vertex Pharmaceuticals; and personal fees from Chiesi Pharmaceuticals and Actavis Pharmaceuticals, outside of the submitted work. NC receives fees plus expenses from the UKCFT in payment for services provided to the UKCFR, including the Pharmacovigilance Programme. DB, NJS, SC, and SBC report fees paid by the UKCFT to their employing institutions for their contribution to the UKCFT Pharmacovigilance Programme.