The United States Food and Drug Administration (FDA) recently finalized guidance on real-world evidence (RWE) and real-world data (RWD) in supporting drug approvals. The guidance predominantly focuses on non-interventional clinical study designs but also outlines what the agency views as potential uses for RWD in interventional studies conducted under an investigational new drug application. The guidance applies to any type of RWD and includes data on products used in clinical practice under an emergency use authorization.
The FDA defines RWD as “data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources.” RWE is defined in the guidance as “clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of RWD.” Additionally, the term interventional study (or clinical trial) is a study in which participants – either healthy volunteers or volunteers with the condition or disease being studied – are assigned to one or more interventions, according to a study protocol, to evaluate the effects of those interventions on subsequent health-related outcomes. A non-interventional study (or an observational study) is a type of study in which patients receive the marketed drug of interest during a routine medical practice and are not assigned to an intervention according to a protocol.
The guidance emphasizes early interaction with the FDA when it comes to the drug development process, particularly if the sponsor is planning to use a non-interventional study to support a marketing application. “Early engagement will help address the appropriateness of using a noninterventional study design and the proposed data sources to address the research question of interest. Additionally, early engagement will allow for timely identification of challenges in the design and planning of a non-interventional study and for discussion of how such challenges might be addressed,” FDA wrote in the guidance.
FDA also recommended that sponsors provide the agency with draft versions of their proposed protocol and statistical analysis plan for review and comment prior to conducting study analyses. Any revisions made to the protocol should be date stamped and should include a rationale for the change. A description of the data sources that were evaluated in designing the study should also be included as well as justification for selecting or excluding data sources. The agency also recommends, in the name of transparency, that sponsors post their study protocol on a public website, such as ClinicalTrials.gov.
If any RWD is used in the drug development, the early conversations with the FDA should include how the agency will be able to access the RWD. Sponsors should have patient-level data for all RWD that is part of a clinical study that will be included in a marketing application. If the RWD is owned by an entity other than the sponsor, there should be agreements in place that will allow the FDA to access the data. If third parties are unable to submit data to the FDA via the traditional channels, the third-party may wish to open a pre-investigational new drug application or Type V drug master file to protect and provide the patient-level data.
The guidance further noted that study monitoring should start at the time the data is extracted from RWD sources, with a focus on protecting human subjects and maintaining data integrity. Minimum requirements for a non-interventional study monitoring include: RWD being accurate and consistent with source records; following the statistical analysis plan, protocol, and study procedures; and documenting any deviations from prespecified plans and protocols (and mediating when necessary). Additionally, if an adverse event is identified during a non-interventional study, it must be reported as part of the postmarketing reporting requirements.
As is often the case, FDA’s guidance documents do not establish legally enforceable responsibilities, but instead describe the agency’s current thinking on a topic and should be viewed as recommendations (unless specific regulatory or statutory requirements are cited).