FDA RWD/RWE regulatory considerations in draft guidance highlight opportunities and challenges

Laying groundwork for high-quality evidence to support regulatory decisions

This month, FDA released the latest in a series of agency guidance to advance the development and use of real-world data (RWD) and real-world evidence (RWE) in clinical trial designs for drug development programs. The draft guidance, “Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products,” discusses the investigational new drug (IND) requirements (21 CFR Part 312) for interventional studies, and recommends early engagement with FDA if non-interventional (observational studies) utilizing RWD are intended to support a marketing application.

FDA’s RWE program has been an agency-wide strategic priority since the program was initiated in 2018, with key advancements under former Commissioners Stephen Hahn, MD, and Scott Gottlieb, MD. FDA chief-nominee Robert Califf stated during his Senate HELP committee hearing earlier in December that, should he be confirmed, creating a system for RWE generation to support healthcare and regulatory decision-making would be a top programmatic priority for the agency. While Dr. Califf acknowledged concerns with FDA’s use of expedited pathways, he clarified that high quality evidence can provide a more efficient way to understand the risks and benefits of medical products when they’re used in practice, including those that come to market through FDA’s Accelerated Approval pathway.

The regulatory considerations discussed in FDA’s guidance and recommendations for non-interventional (observational) studies highlight the significance for sponsors to identify RWD/RWE study needs at early stages of development, and to ensure the studies are well-designed, comply with 21 CFR Part 11 requirements, include appropriate protections for the rights and safety of human subjects, and data integrity is maintained. A key takeaway from FDA’s RWD/RWE guidance is the need for product-specific guidance for certain diseases or serious conditions, such as lung and breast cancer or heart disease, to leverage robust real-world datasets and potentially enrich development for therapies for less common diseases or conditions.

Drug developers, clinical trial sponsors and other life-sciences stakeholders, including digital drug development tool (DDT) developers, should review the guidance and consider submitting comments by March 8, 2022.

Top strategic priority for FDA

FDA’s ongoing RWE program is based on the December 2018 “RWE Framework” which was required under The 21st Century Cures Act (Cures Act) and created a program for evaluating the potential use of RWE to help support the approval of a new indication for an approved drug, or to help support or satisfy post-approval study requirements. RWE generation has been a top strategic priority for FDA since the program formally launched.

If Robert Califf, MD, is again confirmed as the FDA Commissioner, a key priority will be establishing a RWE generation system that relies on electronic health record data to improve patient safety, while also providing an efficient way to understand the risks and benefits marketed drug products. “We’ve got to find the right balance of protecting Americans in a safe way and being innovative in the development of products that can move along quickly, and essential in that part is the development of a better evidence generation system,” said Dr. Califf during his Senate confirmation hearing. He further clarified that he “also want to assure people I’m not talking about willy-nilly analysis of data. I’m talking about well-planned studies, frequently the use of randomization.”

Leveraging RWD/RWE to support drug development and regulatory decision-making were key priorities advanced by former Commissioners Stephen Hahn, MD, and Scott Gottlieb, MD. In Dr. Hahn’s June 1, 2020, remarks on applying lesson learned from the COVID-19 pandemic, the agency advanced collaborations with public and private partner to collect and analyze RWD sources, using FDA’s Sentinel system and other resources, to better understand disease symptoms, describe and measure immunity, use available medical product supplies to help mitigate potential shortages, and inform ongoing work to evaluate COVID-19 vaccines and other potential therapies.

FDA groundwork and challenges ahead

FDA defines RWD as relating to patient health status and/or the delivery of health care routinely collected from a variety of sources, and RWE as the clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of RWD. Examples of RWD include patient-generated data as well as data derived from electronic health records (EHRs), medical claims and billing data, product and disease registries, and other sources that can inform on health status, such as mobile devices.

Historically, FDA has accepted RWE to support drug product approvals only in a limited number of cases, primarily in the setting of oncology and rare diseases. However, as part of its RWE Program, FDA is now evaluating the role of observational studies in contributing to evidence of efficacy via a three-part approach, which includes consideration of whether the RWD are fit-for-purpose; the trial or study design used to generate RWE can provide adequate scientific evidence on the regulatory question; and the study conduct meets FDA regulatory requirements (e.g., for study monitoring and data collection). In July 2021, FDA approved a new use for Prograf (tacrolimus) based on evidence of effectiveness from an RWE observational study with confirmatory evidence from randomized controlled studies. The approval is for use of the drug with other immunosuppressant drugs to prevent organ rejection in lung transplant patients.

Early engagement and transparency with FDA

The series of FDA guidance seeks to address the added complexities for incorporating RWD/RWE studies into marketing submissions, while addressing concerns about its relevance and reliability. FDA acknowledges numerous difficulties that arise from utilizing data from a wide range of information systems with different formats, terminologies, data aggregation methods and overall quality measures. Therefore, the key takeaway from the guidance is early engagement with FDA.

For observational studies that are not subject to FDA’s IND regulations, FDA’s draft guidance outlines the agency’s expectations regarding the design and conduct of such studies including access to relevant datasets, study monitoring, maintaining case records, and early discussions with the relevant review divisions.

In the draft guidance, FDA’s primary advice for observational studies is that sponsors engage with FDA in the early design stages for a study intended to support a marketing application. For example, FDA recommends that sponsors request a Type C meeting, prior to which sponsors should provide draft versions of their proposed study protocol and statistical analysis plan (SAP) for agency review. In order to ensure transparency with FDA regarding RWD collection/analysis, FDA recommends that drug and biologic sponsors document and describe all data sources, analyses and patient characteristics during study design.

FDA also addresses the added complexities for incorporating such information into submissions to the agency, including issues relating to data access, study monitoring, safety reporting, sponsor oversight and data integrity, as well as addressing concerns about its relevance and reliability.

Additional RWD/RWE guidance

In addition to FDA’s considerations guidance, the agency issued three guidance documents over the last few months:

  • In September 2021, FDA issued a comprehensive draft guidance regarding the use of electronic health records (EHR) and medical claims data to support regulatory decisions for drugs and biologics. It provides considerations for defining treatment exposure, outcomes, and other important elements in a study, and also includes considerations for data quality assurance and data quality control procedures.

  • In October 2021, FDA issued the draft guidanceData Standards for Drug and Biological Product Submissions,” addressing preliminary considerations for making regulatory submissions containing study data derived from RWD sources using data standards supported by FDA. It proposes that sponsors seeking to conform RWD to these data standards should consider the data transformations, conversions, or mappings that may be needed to create study datasets in the required format.

  • In November 2021, FDA issued a draft guidance "Real-World Data: Assessing Registries to Support Regulatory Decision-Making or Drug and Biological Products," which offers FDA’s current thinking on the types of issues that should be considered when either designing a patient registry or using an existing registry to support regulatory decision-making. It proposes how to make appropriate selections of data sources, develop, and validate definitions for study design elements, and evaluate data quality throughout the course of the data life cycle.


One theme repeated throughout this year’s RWE guidance is that, when seeking to incorporate RWD to support regulatory decisions for product development, sponsors should consult with FDA early in the planning of a study to discuss FDA expectations for design and conduct.

FDA recognizes the importance of allowing sponsors to leverage data from electronic health records, medical claims, disease registries and digital DDTs. FDA’s learnings from applications and demonstration have informed the RWE guidance, but more research is needed to develop data standards and mapping tools to provide added transparency. FDA will continue to apply lessons from its RWE efforts in recent years including especially the COVID-19 pandemic, to evolve policies for collecting and submitting RWD/RWE to support applications.

Taken together, the RWE draft guidance documents explain how drug and biologic sponsors should prepare protocols and statistical analysis plans ahead of meeting with FDA that explain the reliability, relevance, and comprehensiveness of their data sources, as well as the methodologies used to validate key design elements and maintain quality during data accrual, curation, and transformation to the final data set. Sponsors should also consider the potential impact of linking one or more registries or data systems on the overall integrity of the data used in the clinical trial.


FDA is accepting comments on this latest draft guidance through March 8, 2022. If you may wish to submit a comment, or have any questions on utilizing real-world data in drug or biologics applications, or on clinical study design more generally, please contact any of the authors of this alert or the Hogan Lovells attorney with whom you regularly work.


Authored by Lowell Zeta, Lynn Mehler, Robert Church, and Sally Gu


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