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Understanding the New FDA Guidance for Drug and Biological Product Submissions Containing Real-World Data to Successfully Navigate Regulatory Decisions

On December 13, 2016, the 21st Century Cures Act (Cures Act) was signed into law, to help accelerate the development of medical products (drugs, biological products, and medical devices) for patients. The Cures Act includes a provision, under Section 505F, to evaluate the possible use of real-world evidence (RWE) to support regulatory decisions, either for the approval of an already approved drug (under Section 505(C)) in a new indication or to support post-approval requirements.  

It has become increasingly clear that the use of real-world data (RWD), which is the patient health data collected from sources other than the traditional clinical trial model, is the next step in the evolution of the clinical trial process. With that in mind. in December 2018, the FDA presented a framework for its real-world evidence program. In this framework, the FDA wanted to clarify the differences between real-world data (RWD), and real-world evidence (RWE), which is clinical evidence that is derived from an analysis of the RWD concerning the usage, or the potential benefits/risks, of the drug. This differentiation is necessary because the evidence derived from RWD and will eventually be used to support regulatory decision-making depends on both the methods used to generate the data and the quality and consistency of the data.

Electronic Submissions must follow the Standardized Study Data Guidance

Under section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), clinical study data that are a part of New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), Biologics License Applications (BLAs) and Investigational New Drug Applications (INDs) are being submitted to the Center for Drug Evaluation and Research (CDER) or to the Center for Biologics Evaluation and Research (CBER), must be submitted in an electronic format that the FDA can process, review and archive. All submissions made following the initial applications listed above, including amendments, supplements, and additional reports are also required to follow the standardized study data electronic submission guidelines.

The FDA has provided a Data Standards Catalog that lists all the current standards that the Agency supports so that sponsors or applicants can ensure they are aware of these standards for electronic data submission. Failure by a sponsor or applicant to abide by these standards could result in the FDA issuing either a refuse to file (RTF) for NDAs and BLAs or refuse to receive (RTR) for ANDAs.

Real-World Data and its Application to Support Regulatory Decisions

In the FDA’s real-world evidence program framework and the recently published guidance for “Data Standards for Drug and Biological Product Submissions Containing Real-World Data” dated October 2021, the FDA cites various examples of RWD. These include, but are not limited to, data from electronic health records (EHRs), medical claims and billing data, data from registries, patient-generated data (e.g., from in-home-use settings), and data from other sources such as mobile devices.

The variety of ways that RWD can be collected, as listed above, lends to the obvious challenges with trying to standardize this type of data. Some of the challenges recognized by the FDA include

Err on The Side of Over Documentation – It is Necessary for Success

Whether a sponsor wants to curate their RWD, such as standardizing the coding of adverse events or adjudicating the progression of a disease, or they wish to extract the RWD for integration into a standardized data model, it is imperative they document all processes and underlying rationale that alter the source data in any shape or form. Documentation becomes even more important when terms used for seemingly simple variables like male/female can be defined differently based on how the patient identifies vs. how the data is collected.  In cases where there is a discrepancy between the variable chosen by the sponsor as an RWD source and that which is defined by the FDA data standard, the sponsor will need to document and rationalize the use of the former in the Study Data Reviewer’s Guide (a document that explains the possible reasons or rationale for the variability between sponsor data and FDA standard-defined data). The use of such a guide aims to help the review of the submitted data.

It is expected the FDA will continue to update their guidance(s) regarding the use of RWD and their catalog that defines the standards that sponsors are expected to use. The use of RWD for regulatory decision-making is still evolving. To make sure that sponsors understand the FDA-supported data standards and how they should be applied to data that they generate, it is recommended that sponsors communicate early, and often, with the relevant FDA review division and present them with their plans of submitting RWD to their appropriate drug submissions.     

Prepare for Challenges and Data Mapping Complexities – They are Expected

In the guidance document, the FDA has given examples of cases where sponsors may face challenges in converting RWD into FDA-supported data. Some of these include:

Sponsors are advised to record such challenges using the Define-XML (a file that transmits metadata describing tabular datasets, including human and animal model datasets in the SDTM and/or Standard for Exchange of Nonclinical Data [SEND] standards) and domain data files. A narrative of the issue should also be included in the Study Data Reviewer’s Guide, pointing the reviewers to the Define-XML and domain data files.

The FDA also expects that data regarding race or ethnicity could potentially lead to discrepancies between RWD and FDA-supported standards due to the heterogeneity of the data sources used to collect this information. FDA recommends the following five categories for the collection of race data:

1. American Indian or Alaska Native

2. Asian

3. Black and African American

4. Native Hawaiian or Other Pacific Islander

5. White

However, RWD sources could define race using other terms that do not conform to the categories defined above. In such a case, documentation in the Define-XML file should be used to clearly lay out the process used to convert the non-standardized data to standardized data.

With an escalating amount of interest in using RWD for regulatory submissions and leaning into innovative technologies and processes to push clinical trials into the 21st century as an industry over the past two years, there are new challenges and complexities that we face. Communication between sponsors and the FDA – though always essential – will become increasingly important in order to navigate the evolving regulatory landscape and ensure product development success. And understanding challenges, limitations, and the strict adherence to documenting all processes and rationale is critical as we streamline data and harness the chaos.

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  1. Framework for FDA’s Real-World Evidence Program (December 2018), available at
  2. Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications Guidance for Industry (June 2021), available at Providing Regulatory Submissions in Electronic Format – Standardized Study Data: Guidance for Industry (PDF – 136KB) (June 2021)

Study Data Standards Resources, available at