Registries for Regulatory Decision-Making: Comparing EMA and FDA Guidance on Real-World Evidence
The use of registries as part of real-world evidence is critical for the clinical and regulatory development of medicines. Read this blog post to understand from our regulatory affairs managers and real-world evidence specialists the latest initiatives and guidelines implemented by the EMA and FDA that can support you in shaping your development programs.
Real-world evidence (RWE), derived from real-world data (RWD), plays an increasingly fundamental role in the development, authorization and post-authorization supervision of medicines. In recent years, a number of initiatives have been proposed to explore, develop and frame the use of RWD and generation of RWE to support regulatory decision-making beyond traditional post-authorization commitments.
The Growing Role of Real-World Evidence and Real-World Data in Clinical Research
Although already widely used for disease epidemiology and post-marketing safety monitoring, the use of RWE to demonstrate efficacy and effectiveness for regulatory purposes is still evolving.1 Recently, the European Medicines Agency (EMA) deployed RWE research programs as part of the identified regulatory science research needs, aimed to strategically advance patient access to medicines in partnership with health care systems in the European Union (EU).2 These goals are described in the EMA Network strategy to 2025 that led to the initiation of the coordination center for the EU Data Analytics and Real-World Interrogation Network (DARWIN EU).3,4
RWE was included in approximately 40% of the marketing authorization applications submitted to the EMA in 2018-19, and EU regulators envision this trend will eventually lead to wider use of RWE as a complement to standard clinical research approaches by 2025.1,5 The U.S. Food and Drug Administration (FDA) has already started this work, initially via the 21st Century Cures Act, which resulted in the FDA’s 2018 framework for real-world evidence program.6,7 The FDA issued five draft guidance-to-industry documents in the second half of 2021, thereby initiating the creation of a framework around the use of RWD to support regulatory decision-making, as planned in the 2018 framework.8,9,10,11,12,13
Using Patient Registries as a Source of Real-World Data
Patient registries are an important source of RWD. The EMA has been working for years to encourage the use of registry data, with the initial aim of optimizing research on rare diseases and personalized medicine.14 In October 2021, the EMA issued a guideline on registry-based studies, which is already applied to post-authorization safety and efficacy studies (PASS and PAES).15
In parallel with the EMA in November 2021, the FDA issued a guidance for industry presenting specific patient registries and how they can be used to support regulatory decision-making, as part of their overall real-world data and real-world evidence framework.9
A brief comparison on some key aspects contained in the EMA and FDA guidelines on real-world data and real-world evidence is presented in the table below.
|EMA Guideline||FDA Draft Guidance|
|Registry Definition||Patient registry: Organized system that collects uniform data (clinical and other) to identify specified outcomes for a population defined by a particular disease, condition or exposure. The term ”patient” highlights the focus of the registry on health information. It is broadly defined and may include|
• patients with a certain disease,
• pregnant or lactating women, or
• individuals presenting with another condition, such as a birth defect or a molecular or genomic feature.
|A registry is defined as an organized system that collects clinical and other data in a standardized format for a population defined by a particular disease, condition or exposure.|
|Approach||The EMA is introducing patient registries as a data source to generate registry-based studies. Registry-based studies are defined by the EMA as investigations of a research question using the data collection infrastructure or patient population of one or several patient registries and can be used for:|
• Supporting clinical trial optimization
• Post-authorization commitment (post-authorization safety studies, post-authorization efficacy studies)
|The FDA’s guidance on registries is part of an overall framework regarding the use of RWD to generate RWE in support of regulatory decision-making that includes:|
• Review of other RWD sources
• Practical aspects and acceptability of RWE for regulatory purposes, e.g., data standardization and submission process
|Type of Registry-Based Studies||Registry-based studies can be interventional, low-interventional or non-interventional studies.||Registry data can ultimately be used to inform the design and support the conduct of either interventional studies (clinical trials) or non-interventional (observational) studies.|
|Use of Registry Data||• Complementing the evidence generated in the pre-authorization phase (e.g., contextualize the results of uncontrolled trials)|
• Providing evidence in the post-authorization phase (post-authorization safety studies, post-authorization efficacy studies)16
• Evaluating the effects of medicinal products used during pregnancy and breastfeeding
|• Characterizing the natural history of a disease|
• Helping determine sample size, selection criteria and study endpoints when planning an interventional study
• Selecting suitable study participants to include in a clinical trial
• Identifying biomarkers or clinical characteristics associated with important clinical outcomes of relevance
• Supporting, in appropriate clinical circumstances, inferences about safety and effectiveness in the context of:
o Non-interventional studies evaluating a drug received during routine medical practice
o Controlled trials including registry data as an external control arm
|Communication with Regulatory Authorities||Early consultation and engagement with national competent authorities and EMA are recommended.||Early consultation and engagement with the FDA are recommended.|
A brief comparison on operational guidance from the EMA and FDA on real-world evidence and real-world data quality, ethics/institutional review boards (IRBs) and data protection, as well as governance, is provided below.
|EMA Guideline||FDA Draft Guidance|
|Data quality||Standards still to be issued||Provided specific guidance on RWD standards12|
|Ethics/IRB and data protection||• Responsibility of the registry owner|
• Sponsor should check that all approvals are obtained
• Informed consent needs to be obtained from patients to participate in the registry-based study in addition to the consent already given for participating in the registry, as applicable.
|• Responsibility of the registry owner; IRB approval recommended for registry data collection.|
• Sponsors also should ensure that a registry adheres to applicable jurisdictional human subject protection requirements, including protecting the privacy of patient health information
The EMA guideline focuses on aspects that are relevant to the European regulatory context, such as details of ethics and data privacy, application of good pharmacovigilance practices (GVP) guidance on PASS/PAES and European Network of Centres of Pharmacoepidemiology and Pharmacovigilance (ENCePP) methodological guidelines, and adverse event reporting.16,17 It also describes governance models.
The FDA guidance focuses on use cases, relevance and reliability of data, a list of key data availability, and possibilities of data linkages. Other aspects, such as overall use of RWE, methodology, governance, data quality and standardization, are addressed in other guidance within the FDA RWE framework.
Use Cases for Registry Data or Registry-Based Studies
EMA guidelines also point to how registry-based studies can be leveraged to complement clinical development data collected in the context of investigational cell and gene therapy and orphan investigational medicinal products, where often only single-arm trials are possible. The FDA guidance goes even further to provide use cases, including serving to generate external control arms to single-arm trials.
Of note, post-marketing obligations to generate RWD for long-term safety (and/or efficacy and therapy durability) exist for all the advanced therapy products marketed in the EU and U.S. in the past few years. One way of accomplishing these is via creation of a registry and conduct of registry-based studies. Recently, the EMA Committee for Advanced Therapy identified a priority to understand “the use of RWD including natural history data, retrospective patient level treatment data and registry-based data in regulatory decision making pre-and post-authorization and in patient access to advanced therapy medicinal products”.18
It can be argued that the attention for adoption of real-world evidence regulatory process has also been enhanced by medicine and vaccine developers to fight the SARS-CoV-2 pandemic. In addition to the EMA and FDA, various regulatory authorities have been looking at implementing the use of real-world evidence to support clinical development, a recent example of which is the guidance on the use of real-world data in clinical studies published by the United Kingdom’s Medicines & Healthcare products Regulatory Agency (MHRA) in December 2021.19
Early Engagement and Collaborations
Considering the evolving and diverse regulatory frameworks across jurisdictions, sponsors are encouraged to engage with regulatory agencies and other stakeholders — such as registry holders and health technology assessment bodies, ideally through joint scientific advice procedures, when applicable, such as EMA/FDA parallel scientific advice or integrated scientific advice — when planning to conduct registry-based studies.
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