Patient Registries for PV
Reprint from PIPELINE Issue 56; September 2018 © Copyright Pharmaceutical Information and Pharmacovigilance Association. All rights reserved.
Patient registries are nothing new but are quite disparate from their inception through to maintenance and utilisation. From small spreadsheets capturing minimal data to huge, purpose-built databases, patient registries take many forms. Often developed independently by individual stakeholders, the current world of patient registries is ripe for the introduction of efficiencies, whether that be reducing duplication of effort or closer collaboration of parties. With increasing numbers being requested as part of licence conditions, they have become a focus for the European Medicines Agency (EMA) in terms of optimising their use and development. Here, we take a brief look at the recent evolution of patient registries and some key milestones in the EMA’s strategy.
Patient registries are organised systems that use observational methods to collect uniform data on a population defined by a particular disease, condition, or exposure, and that is followed over time[1]. They are particularly useful when a disease or product exposure are rare, or in special populations (such as paediatric or pregnancy). Either voluntary, or imposed as a condition of authorisation, the use of patient registries form an important part of the methodology available to Marketing Authorisation Applicants (MAAs)/Marketing Authorisation Holders (MAHs) looking to fulfil their pharmacovigilance (PV) obligations, whether that be for Post Authorisation Safety Studies (PASS), assessing the impact of risk management plans (RMPs) etc. Between 2005-2013 approximately 9% of authorised products had a registry as an imposed requirement[2].
Registries can be broadly split into two types[3] :
- Disease registries - include patients based on diagnosis, for instance the Drug Induced Arrhythmia Risk Evaluation (DARE).
- Product registries - include patients based on the treatment they receive, for instance the Rivaroxaban Observational Safety Evaluation (ROSE).
Although the distinction between the two approaches is imprecise, disease registries may often be preferred by regulators as they allow for comparisons between treatments (i.e. case-control or cohort studies) rather than just standalone data on a specific product. An inventory of patient registries, within the European Union (EU), is available at the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)[4]. It is not comprehensive, and owners of registries not currently included are encouraged to add them.
Good Pharmacovigilance Practice (GvP) Module VIII ‘Post-authorisation safety studies’ gives some guidance on the use of patient registries as part of a company’s PASS strategy. It is important to note that PASS and patient registries are distinct entities and the relevant sections of Module VIII are related to the use of registry data in PASS, rather than the design of registries themselves. As described above, patient registries are a method of data collection, that may or may not be used as part of a PASS. A PASS itself may utilise the data available through a patient registry, but specifically tests a hypothesis using rigorous methodology via a PRAC approved protocol. For any PASS using registry-derived data, the choice of the registry population should be driven by its objective(s) in terms of outcomes to be measured and analyses and comparisons to be performed[5]. Where a registry is being set up to facilitate a specific PASS, the design of the registry should be driven by the same criteria.
EMA Initiative for Patient Registries
This initiative had two components: a strategy on registries and a pilot phase to test whether this strategy better supports MAAs/MAHs to meet regulators’ (and potentially other stakeholders’) needs for data and information; “to facilitate the use of existing patient registries and facilitating the establishment and utility of new registries if none are available or adequate, in order to collect and analyse high quality data informing regulatory decisions[1].”
Strategy
The strategy planning was initiated in 2014, to address the key challenges faced by regulators and companies when utilising existing or establishing new patient registries. In December 2014, a cross-committee task force made up of multiple stakeholders (including the Pharmacovigilance Risk Assessment Committee (PRAC) and Committee for Medicinal Products for Human Use (CHMP)) was set up to support the five-point strategy[1]:
1. Early dialogue with MAAs/MAHs
2. Definition of data collection characteristics by or with the committee or working party: objectives, population, outcomes, any hypotheses to be tested; as appropriate, input from different stakeholders may be considered
3. Identification of existing data sources that could fulfil the objectives, and evaluation of their adequacy by MAAs/MAHs in collaboration with regulatory authorities and data source custodians
4. Identification of the need for data or information that is best addressed through a registry
5. a. Amendment or addition to existing registry/registries
b. Definition of core components of a new registry.
A mandate for the task-force was finalised in May 2017[6].
Pilot Phase
The pilot phase was launched in September 2015, to test the agreed strategy. By April 2016, four case studies had been identified[7].
In October 2016, a workshop of key stakeholders was held to discuss the challenges and barriers to collaboration and identify specific solutions[8]. Multiple recommendations were made during the workshop, which confirmed the wish for regulator guidance and endorsement of registries. The EMA came away with seven activities to initiate: including bringing together the stakeholders for the identified case studies.
To date, the reports of workshops have been published on three of the case studies; cystic fibrosis (CF)[9]; multiple-sclerosis (MS)[10]; and Chimeric Antigen Receptor T-cell (CAR T-cell) therapies[11].
Conclusions
The conclusions have been somewhat different across the trials but provide important insights into the next steps for optimising existing disease registries and initiating new ones. For instance, the CF registry landscape was found to be “collaborative and mature”. In comparison, the MS landscape was more heterogenous, but with plenty of support for greater collaboration and optimisation. CAR T-cell therapies were found to pose greater challenges to utilising existing registries due to the need for long-term follow-up. However, this could offer welcome opportunities to define what will be required from the beginning, rather than having to awkwardly adapt existing sources of information.
While the recommendations in each case study differ in their specifics, overarching conclusions and future actions remain consistent[12]:
- A willingness to move from the traditional model of a single company registry to collaborative efforts, involving all stakeholders, allowing for long-term follow-up.
- Improving data quality in existing registries and defining quality in new ones.
- A qualification process involving EMA scientific advice would also aid trust and confidence in registry data (for instance, as has been drafted for The European Cystic Fibrosis Society Patient Registry (ECFSPR)[13])
- Understanding of differing expectations of what data is collected, between different stakeholders. As with the EMA priority medicines (PRIME) scheme, early access to regulators for registry holders can help ensure everyone is on the same page.
- The EU regulatory network to develop tools to support the use of registries
It is an exciting time for the use of patient registries, making post-marketing pharmacovigilance much more proactive and effective, rather than the traditional model of over-reliance on spontaneous reports. As you can tell from the number of documents referred to in this article, there is a lot of information being produced on the topic and few conclusive answers on exactly what the future will look like. However, it is heartening that there is such enthusiasm and buy-in from all sides and collaboration and communication with regulators is the order of the day. Fingers-crossed those of us in the UK get to enjoy that EU spirit for more than a couple more years!
Drive Phase PV is a pharmacovigilance consultancy and provider of pharmacovigilance services, supporting patient safety throughout the life-cycle of our clients' products. Contact us to discuss optimising your use of patient registries. Whether via SOP development or provision of training, we deliver a tailored packaged to seamlessly fit to your company structure and strategy.
1 EMA Initiative for patient registries (http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/10/WC500195576.pdf)
2 Registries in European post‐marketing surveillance: a retrospective analysis of centrally approved products, 2005–2013 (https://onlinelibrary.wiley.com/doi/full/10.1002/pds.4196)
3 Drug Safety Research Unit (http://www.dsru.org/studies-for-risk-management/registries/)
4 http://www.encepp.eu/encepp/resourcesDatabase.jsp
5 Good Pharmacovigilance Practice Module VIII Post-authorisation safety studies (Rev 3) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129137.pdf
6 Patient Registry Initiative- Strategy and Mandate of the Cross-Committee Task Force (http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/05/WC500227793.pdf)
7 Briefing note to marketing authorisation holders/ applicants on the EMA Patient Registry Initiative (http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/04/WC500204908.pdf)
8Patient Registries Workshop Report 28 October 2016 (http://www.ema.europa.eu/docs/en_GB/document_library/Report/2017/02/WC500221618.pdf)
9 Report on cystic fibrosis registries (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000658.jsp&mid=WC0b01ac0580961211#)
10 Report on multiple sclerosis registries (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000658.jsp&mid=WC0b01ac0580961211#)
11 Report - CAR-T cell therapy registries workshop (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000658.jsp&mid=WC0b01ac0580961211#)
12 Use of disease registries for benefit risk evaluation of medicines: A regulatory perspective (http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2018/05/WC500248501.pdf)
13 Qualification Opinion The European Cystic Fibrosis Society Patient Registry (ECFSPR) (http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2018/02/WC500243542.pdf)