The new FDA guidance on the use of real-world data (RWD) and real-world evidence (RWE) is a long-anticipated playbook for how a drug manufacturer can employ a non-interventional study for regulatory decision-making. The process is not as simple as extracting observational data from a registry, although the benefits are potentially immense given that the sponsor can avoid the need for an expensive and cumbersome randomized controlled clinical trial (RCT).
The scope of the guidance includes biologics and pharmaceuticals, which are jointly referred to in the guidance as drug products. However, the guidance does not include devices or in-vitro diagnostics, although the FDA published a parallel guidance for medical devices in 2017. The FDA Oncology Center of Excellence is listed as one of the Agency’s participant offices, but this guidance applies principally to the use of RWE and RWD for post-approval studies and for expansion of the labeled indication for a drug product that has already been granted market authorization.
Definitions a Key Starting Point
The guidance was prompted by the 21st Century Cures Act and defines RWD as data from a variety of sources relating to patient health status and/or delivery of healthcare services. The definition of RWE is any clinical evidence about the usage of and potential benefits and risks of a medical product derived from an analysis of RWD.
The definitions of interventional studies and observational studies are also essential for the purposes of this guidance. An interventional study is defined as a study in which the participants are actively assigned to the treatment or an alternative—either a comparable treatment or a placebo. In contrast, a non-interventional study, or observational study, makes use of data derived from routine clinical use of the drug in question. While interventional studies require that the FDA has granted an investigational new drug (IND) or similar application, an observational study typically will not require an IND. However, this type of study must still be registered at a clinical study database, such as the U.S. national clinical trials database, and must comply with both institutional review board requirements along with requirements for the protection of human subjects.
The types of data that can be used in an observational study include:
- Registry data, such as the Transcatheter Valve Therapy (TVT) registry;
- Electronic health record data, which may have to be purchased from the host healthcare institution; and
- Healthcare claims data, such as Medicare claims data, which are publicly available.
While RCTs are typically much more costly to conduct than observational studies, the process of obtaining secondary data is rarely instantaneous and inexpensive. One of the issues with using multiple data sets is that the data are not always interoperable, which may increase the data processing cost. Another caveat is that an observational study that is amended such that the patient’s treatment is altered becomes an interventional study because the drug is no longer being used strictly in the routine practice of medicine.
Agency Suggests Early Interaction to Streamline Review Process
The FDA recommends that the sponsor contact the Agency about a non-interventional study while the study is still in the planning stages, and that the sponsor provide a draft version of the protocol and statistical analysis plan. One of the key considerations for the FDA in reviewing these documents is the need to determine whether a database was excluded from the study to bias the outcome in a specific direction. However, the Agency will also examine the proposal to ensure that the selected data sets are appropriate for the underlying research question.
Similarly, the sponsor is expected to provide details on the selection or exclusion of data sources from its study along with a review of the analytical approaches selected for processing the data. The draft form of the statistical analysis plan should be submitted to the FDA along with the draft study protocol.
Type V Drug Master Files a Resource for Patient-Level Data
The FDA expects that the sponsor will be able to provide patient-level data with any application making use of RWE/RWD, a stipulation that also applies when an outside entity owns the data. The data should be available for inspection by the Agency, and can be submitted by one of several means, such as with the submission of a Type V drug master file.
These observational studies come with study monitoring requirements, such as procedures to ensure that:
- The RWD required by the protocol are accurate and consistent with source records;
- Prespecified plans and study procedures were followed; and
- Any deviations from the plans and procedures are documented, evaluated, and, when appropriate, remedied.
While the sponsor of the non-interventional study is generally responsible for reporting any postmarket safety reporting requirements for adverse events (AEs), the sponsor is not responsible for AEs that do not appear in the subset of data drawn from a larger database. The Agency explained that the sponsor of the observational study is not expected to search that entire database for AEs that would qualify for reporting to the FDA, but is liable for reporting any events associated with the patient records used in the observational studies.
Part 11 Requirements Apply to Observational Studies
The electronic systems used in these observational studies must be in compliance with Part 11 requirements for electronic signatures, and sponsors should document the names and qualifications of researchers involved in the study. However, there are several interlocking guidances associated with this guidance, such as the 2003 guidance for Part 11 considerations. The FDA also highlighted the 2018 guidance for the use of electronic health records in clinical investigations, and the March 2023 draft guidance for electronic systems and electronic signatures used in clinical investigations.
There are several other interlocking guidances captured by this guidance for RWE and RWD, including yet more guidances that are still in the draft stage. Among the documents on this list is the September 2021 draft guidance for the assessment of the quality of RWD in drug and biologics applications, so the applicant who wishes to make use of this latest FDA guidance has a considerable regulatory thicket to manage. Nonetheless, the ever-increasing flow of patient data in the U.S. and other developed nations provides a treasure trove of information that can help the manufacturer efficiently optimize its investment in that product, an objective that this new guidance enables.
