This guidance provides recommendations to sponsors and investigators who are considering submitting a non-interventional study, also referred to as an observational study, to FDA to contribute to a demonstration of substantial evidence of effectiveness and/or evidence of safety of a drug. Specifically, this guidance discusses attributes regarding the design and analysis of a non-interventional study that sponsors should consider when proposing a non-interventional study for such regulatory purposes.
In this guidance, a non-interventional study is a type of study in which patients receive the marketed drug of interest during routine medical practice and are not assigned to an intervention according to a protocol. Examples of non-interventional study designs for evaluating the effectiveness and/or safety of a drug include, but are not limited to, (1) observational cohort studies in which patients are identified as belonging to a study group according to the drug or drugs received or not received during routine medical practice, and subsequent biomedical or health outcomes are identified; (2) case-control studies in which patients are first identified as belonging to a study group based on having or not having a health-related biomedical or behavioral outcome, and antecedent treatments received are then identified; and (3) selfcontrolled studies (e.g., case-crossover5 and self-controlled case series), where the same person serves as their own control.
The reliability and relevance of real-world data (RWD)7 used in a non-interventional study are critical for making appropriate causal inferences and are essential to establishing the data’s fitness for use in generating real-world evidence to support a labeling change or address a safety concern. When considering RWD, the term reliability includes accuracy, completeness, and traceability; the term relevance includes the availability of data for key study variables (exposures, outcomes, covariates) and sufficient numbers of representative patients for the study. FDA has published guidances addressing corresponding issues related to fitness for use (i.e., reliability and relevance) when using electronic health records (EHRs) and medical claims data as well as data from registries to support regulatory decision-making. The Agency has also published a guidance on considerations for using data standards that are currently supported by FDA in applicable drug submissions containing study data derived from RWD sources.
Additionally, FDA published a guidance that describes regulatory considerations for non interventional studies involving the use of RWD, including RWD access, study monitoring, safety reporting, and other sponsor responsibilities. Two issues discussed in the previously published guidance are particularly relevant in the design phase of a non-interventional study: the importance of (1) prespecification of study design and conduct and (2) early engagement with FDA to help address the appropriateness of using a non-interventional study design to address the research question of interest for the proposed indication. The topics discussed here should be considered in conjunction with the recommendations in all of these other guidances.
This guidance addresses the growing interest in the potential use of non-interventional studies to support the demonstration of the effectiveness of a drug. FDA has previously published a guidance describing best practices specific to conducting and reporting on pharmacoepidemiologic safety studies that use electronic health care data to assess the risk associated with a drug exposure. The broad epidemiologic principles presented here may also 61 be relevant to pharmacoepidemiologic safety studies.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
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