The US Food and Drug Administration (FDA) issued draft guidance, providing recommendations to sponsors who are considering submitting a non-interventional study (i.e., an observational study) to FDA to support the demonstration of substantial evidence of effectiveness and/or evidence of safety of a drug or biologic, as another chapter in its evolution toward the use of real-world evidence (RWE).

FDA acknowledges the growing interest in using non-interventional studies to support regulatory submissions and outlines considerations when planning to use non-interventional studies, the types of data that may be appropriate to use, and how to address potential challenges associated with planning and conducting such studies.

Importantly, FDA emphasizes the need for reliability and relevance of data when determining whether the data is appropriate to support regulatory submissions. Highlighting an area of concern for non-interventional studies generally, FDA discusses the need to ensure that confounding or other forms of bias do not introduce error into study results in this context. Referencing earlier RWE guidance from FDA, the agency notes the importance of prespecification of study design and conduct and early engagement with the agency regarding the use of these study designs.

In this guidance, FDA defines a non-interventional study as a study in which patients receive the marketed drug of interest during routine medical practice and in which patients are not assigned an intervention determined by a protocol. The guidance discusses important attributes of a non-interventional study design and analysis that sponsors should consider when using these types of studies to support the substantial evidence standard. FDA proposes that sponsors provide information on the following:

• Summary of the proposed approach, which includes a finalized study protocol, the research question of interest, identification of (and rationale for) the study design, information on alternative study approaches (and why these alternative approaches were not feasible), and other information assessing whether the proposed study is fit for use to address the research question
• Key study design elements, which includes the source population (i.e., the population from which the study population will be drawn), eligibility criteria, relevant covariates (e.g., concominant treatments), and strategies to address potential bias
• Data sources and their appropriateness and limitations, which includes a description of the proposed data sources, rationale for choosing the data sources, relevance of the data to the drug of interest, appropriateness of the information on confounding factors, and available information on data reliability, among other things
• Analytic approach—or a prespecified statistical analysis plan (SAP)—which “address[es] the specific study objectives and detail[s] the primary analysis and any secondary analyses.” The draft guidance includes recommendations on the data elements to be included in connection with the SAP

Recommendations

Sponsors that are considering submitting marketing applications that intend to use a non-interventional study are strongly encouraged by FDA to discuss its plans early with the agency related to the appropriateness of using the study design to address the research question for the proposed indication. Considering previous FDA guidance on the use of real-world data to generate RWE, sponsors can expect FDA to continue providing additional clarity on the use of RWE to support a drug or biologic product approval. Interested stakeholders should also comment on this draft guidance, with the comment period scheduled to close on June 20, 2024.