By John Concato, MD, MPH, MS, Associate Director (Real-World Evidence Analytics), Office of Medical Policy, and M. Khair ElZarrad, PhD, MPH, Director, Office of Medical Policy

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Collection and analysis of real-world data (RWD) continue to gain traction in the biomedical community, accompanied by a growing understanding of RWD’s strengths and limitations. Increased collection of RWD is leading to the generation of real-world evidence (RWE) that can potentially inform regulatory decisions regarding the safety and effectiveness of medical therapies. Such regulatory decisions include whether to approve the drug, what the drug’s indication(s) should be, and what safety protocols (if any) are necessary to ensure safe use of the product. As defined by FDA, RWD are the data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources and RWE is the clinical evidence regarding a medical product’s use and potential benefits or risks derived from analysis of RWD.

To promote progress in the field and address a congressional mandate, FDA is issuing a series of draft guidances for industry on aspects of RWD and RWE in regulatory decision-making. The agency issued four of these guidances in late 2021 and plans to issue more guidance in the future. The guidances released so far cover topics related to data sources, data standards, and regulatory considerations.

Draft Guidances on Data Sources

One draft guidance in this series, Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products, outlines considerations for using RWD from electronic health records (EHRs) and medical claims, which have been a component of safety studies for a long time and are recognized as having certain limitations. These same limitations apply, and often have a greater impact, when using RWD in effectiveness studies. Cognizant of the inherent challenges of using such data in research, investigators have been developing improved approaches to generate valid evidence.

This guidance provides recommendations on how to select relevant data sources as well as to define and validate study variables, including population eligibility criteria, treatments, and outcomes. The guidance also provides recommendations on ways to maintain the provenance (intactness) and quality (reliability) of the data from collection to curation in a data repository and ultimately to a specific dataset for analysis of the research question.

FDA has also published a draft guidance on RWD from registries titled Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products. Registries are another important source of RWD, as they collect clinical and other data from a population with a certain disease, condition, or medication exposure. These data are obtained from health care providers or patients and sometimes are linked to other data sources, such as EHRs or medical claims data.

This guidance provides recommendations on designing a registry or using a pre-existing one to support regulatory decision-making. As with the guidance discussing data from EHRs or claims, this guidance provides considerations for how a registry can be “fit-for-use” (i.e., reliable and relevant) in regulatory contexts. The guidance also discusses challenges when linking a registry to another data source for supplemental information, including resolving inconsistencies, protecting patient privacy, and reducing redundancy.

Draft Guidance on Data Standards

After sponsors obtain RWD, they typically need to standardize the information for analyses that can ultimately yield clinically relevant evidence. This task involves addressing potential inconsistencies involving formats, terminologies, and algorithms in different RWD sources. The draft guidance, Data Standards for Drug and Biological Product Submissions Containing Real-World Data, addresses considerations for complying with relevant legal requirements by using FDA-supported data standards in applicable drug submissions that contain study data derived from RWD.

When standardizing variables in RWD, the guidance advises sponsors to document their rationale and to note the challenges they faced and changes they made to the data to conform to FDA-supported data standards. The guidance also recommends creating a “data dictionary” with definitions for the data elements.

Draft Guidance on Regulatory Considerations

Working with RWD can involve study designs other than clinical trials, where participants are assigned the treatment of interest according to a research protocol. In this context, FDA has issued the draft guidance, Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drugs and Biological Products with an emphasis on regulatory considerations for non-interventional (observational) studies.

This draft guidance notes that interventional studies using RWD are generally subject to FDA’s investigational new drug application (IND) regulations. An example is an externally controlled trial, wherein outcomes of participants in a treatment group are compared to outcomes among an external group of people who are not in the same trial — either data from participants in an unrelated trial or RWD from patients receiving routine medical care.

The guidance also describes FDA’s expectations regarding non-interventional studies that use only RWD. Although these studies are not subject to FDA’s IND regulations, their quality, reliability, and integrity will affect how FDA considers the evidence submitted in a marketing application. This guidance covers issues such as finalizing a study protocol and analysis plan before conducting the study, maintaining study records, and making sure FDA can access and verify those records.

Going Forward

In the future, FDA intends to issue guidance on designing studies that use RWD, specifically externally controlled trials and randomized controlled trials conducted in clinical practice settings.

With the issuance of this series of RWD/RWE draft guidances, the agency expects that drug sponsors, health care providers, patients, and the public at large will have a greater understanding of how RWD and RWE can fit into the regulatory process. The agency is already using RWE for regulatory decisions, and we will continue to consider how to optimally incorporate RWD and RWE to provide trustworthy information about the safety and effectiveness of drug therapies.