The U.S. Food and Drug Administration (FDA) issued its third draft guidance under the Real-World Evidence (RWE) Program on November 29, 2021. In Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drugs and Biological Products, the FDA discusses considerations for sponsors and other stakeholders when designing or using an existing registry as RWD to support a regulatory decision about the safety and effectiveness of a medicine or biologic.
The goal of the RWE program, in part, is to satisfy Congress’s mandate under section 505F of the Federal Food Drug and Cosmetic Act (FD&C Act) for the FDA to provide more guidance about the use of RWE in regulatory decision-making. We discussed the FDA’s first and second guidances, released in August and October 2021, here and here.
Registries are “organized systems that collect clinical and other data in a standardized format for a population defined by a particular disease, condition, or exposure.” To establish a registry, companies enroll a predefined “population” into the registry and then collect prespecified health-related data for each individual patient in that population.
The guidance is designed to ensure that sponsors and companies properly use registries as RWD to support regulatory filings. A registry’s usability in the regulatory context depends in large part “on how the data are intended to be used, the patient population enrolled, the data collected, and how the datasets were created, maintained, curated, and analyzed.”
The guidance is organized into five parts.
A: Using Registry Data to Support Regulatory Decisions
The FDA states that sponsors should consider both the strengths and limitations of using registries as a source of data to support regulatory decision-making. Registries may have advantages over other RWD sources because they collect structured and predetermined data elements, which can offer longitudinal, curated data about a defined population. They also can systematically collect patient-reported data that other datasets may not have identified. However, registries can also have limitations. For example, existing registries may focus on one disease but have limited information on comorbidities.
The FDA explains that registries are better suited as a data source for regulatory purposes when sponsors aim to collect objective endpoints, such as death or hospitalizations, rather than subjective ones like pain. Subjective points may be collected, but there are challenges to standardize these measurements.
Before using any RWD (including registry data) for regulatory decision-making, sponsors should consider whether the data are fit for use by assessing the data’s relevance and reliability.
B: Relevance of Registry Data
The guidance defines “relevance” as “availability of key data elements (patient characteristics, exposures, outcomes) and a sufficient number of representative patients for the study.” When considering whether a registry is suitable to use as RWD in a regulatory context, a sponsor’s overall assessment of relevance should include whether the registry is adequate to evaluate the scientific objective.
The assessment of data’s relevance is context dependent. For example, if a sponsor wants to use a registry for a regulatory purpose, it should consider the methods of patient selection for the registry and the impact these methods have on the representation of the population. Sponsors should consider which data elements a registry has and should have based on their intended use for the registry.
The FDA’s non-exhaustive list of potential data to include in a registry includes:
- Demographic and clinical information
- Treatment information for the disease of interest (if applicable)
- Health-related outcome information
- Pregnancy-related information (if applicable)
C: Reliability of Registry Data
The guidance defines “reliability” as “data accuracy, completeness, provenance, and traceability.” Sponsors should ensure processes are in place to ensure the reliability of registry data, including procedures to govern registry operation, education and training of registry staff, and resource planning.
The FDA provides a list of items it considers when assessing reliability, such as how data is collected (data accrual), whether the registry processes and personnel can ensure data integrity, and whether sponsors have security and privacy controls in place to protect confidentiality and privacy of data. Additionally, sponsors should periodically address indicators of “data consistency, accuracy, and completeness.”
D: Considerations When Linking a Registry to Another Registry or Another Data System
The draft guidance next outlines considerations for how sponsors might link one registry to another, or to a different type of RWD source, such as electronic health records. For example, if a registry does not capture the necessary information, sponsors should consider supplementing the registry with data from other sources, such as another registry or medical claims database, or digital health technologies with sensors that track and monitor health information.
When linking data, sponsors should consider the potential impact of the new data on the overall integrity of the registry data, and use strategies to correct redundant data, resolve inconsistencies, and address other potential issues, such the secure transfer of private patient information.
E: Considerations for Regulatory Review
Sponsors interested in using registry data to support a regulatory decision should meet with the FDA before conducting a study that will include registry data. Topics the FDA advises sponsors be ready to discuss include the ability of the data to evaluate the target population, where the data elements come from and the frequency and timing of data collection.
Sponsors also should provide protocols and statistical analysis plans that include essential elements of a registry study’s design, analysis, and conduct. Additionally, if the registry data are owned and controlled by a third party, the sponsor should have an agreement in place to ensure all relevant patient-level data can be provided to the FDA and source records are made available for inspection.
Comments are open until February 28, 2022. Several trade associations and the RWE Alliance (including Aetion, an RWE company the FDA collaborates with, which we discussed here) have asked the FDA to extend the comment period for the RWD sourcing guidance.
Faegre Drinker’s life sciences industry group continues to monitor RWD and RWE news, and provide updates as they become available.