Real-World Evidence for USFDA Approval

Randomized Clinical Trials (RCT) provide the best evidence of the efficacy of a drug to support regulatory decisions for product approval. RCT overcomes biases encountered in a study, such as selection bias. On the other hand, Real-World Data (RWD) collects data from diversified areas of a patient’s daily life that are outside the scope of RCTs.

The US Food and Drug Administration (USFDA) defines Real-World Data (RWD) and Real-World Evidence (RWE) as follows:

  • RWD are data relating to patient health status and/or the delivery of health care routinely collected from various sources.
  • RWE is the clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of RWD.

RCT involves predefined selective populations, whereas RWD is a real-world practice. RCTs are usually interventional studies, and RWD is non-interventional.

USFDA defines an interventional study (also referred to as a clinical trial) as a study in which participants, either healthy volunteers or volunteers with the condition or disease being studied, are assigned to one or more interventions according to a study protocol to evaluate the effects of those interventions on subsequent health-related outcomes. On the other hand, a non-interventional study (also called an observational study) is one in which patients receive the marketed drug of interest during routine medical practice and are not assigned to an intervention according to a protocol.


USFDA Guidance

The USFDA  issued a final guidance for the industry titled Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drugs and Biological Products. The guidance outlines the agency’s general expectations for study conduct for non-interventional (observational) studies, which are not subject to FDA’s IND regulations. The salient points are-


The USFDA discusses the applicability of part 312 (Investigational New Drug Application) in guidance to RWD studies.

  • USFDA regulations under part 312 define a clinical investigation as “any experiment in which a drug is administered, dispensed to, or used involving one or more human subjects. For this part, an experiment is any drug use except for a marketed drug during medical practice.”
  • USFDA recognizes the potential utility of using RWD in interventional studies;
  • Non-interventional studies analyze data reflecting the use of a marketed drug administered in routine medical practice, according to a medical provider’s clinical judgment and based on patient characteristics, rather than the assignment of a participant to a study arm according to a research protocol. As such, non-interventional studies are not clinical investigations as defined under § 312.3 and do not require an IND.
  • Certain non-interventional studies include protocol-specified activities or procedures (e.g., questionnaires, laboratory tests, imaging studies) that collect additional data to help address questions of interest in these studies. FDA does not consider these types of studies to be clinical investigations under part 312, and an IND is not required

Transparency Regarding Data Collection and Analysis

  • Sponsors planning to use a non-interventional study to support a marketing application should engage with USFDA early in the drug development using an appropriate regulatory pathway (e.g., requesting a Type C meeting through an existing IND). Early engagement will not only help address the appropriateness of using a noninterventional study design but also allow for the timely identification of challenges in the design and planning of a non-interventional study and for discussion of how such challenges might be addressed.
  • USFDA must be confident (based on corresponding documentation) that particular data sources or databases were not selected or that specific analyses were not conducted to favor a particular conclusion to adequately assess the results of a non-interventional study supporting a marketing application. The protocol and SAP should be finalized and shared with USFDA before conducting the prespecified analyses described in the protocol and SAP. In addition, any revisions to the protocol should be date-stamped, and the rationale for each change should be provided to USFDA. To ensure transparency regarding their study design, sponsors should post their study protocols on a publicly available website, such as or the web page for the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP) for post-authorization studies.
  • In the early stages of designing a non-interventional study intended for use in a marketing application, sponsors should discuss the expectations regarding access to RWD used in their development program with the relevant review division. Sponsors must ensure they can submit patient-level data for any RWD analyzed as part of the clinical study included in a marketing application when required under 21 CFR 314.50 and 601.2. Sponsors should ensure that RWD and associated programming codes and algorithms submitted to the FDA are documented, well-annotated, and complete, allowing the FDA to replicate the study analysis using the same dataset and analytic approach.
  • As part of study monitoring of a non-interventional study, sponsors should, at a minimum: − Ensure that the RWD required by the protocol is accurate and consistent with the source records − Ensure that prespecified plans (e.g., SAP), protocol, and study procedures (e.g., for curation and transformation and reporting of results) were followed − Ensure that deviations from the prespecified plans and protocol and study procedures are identified and documented, and when necessary, promptly evaluated and remediated according to the significance of the deviations that have been identified.
  • Sponsors who submit non-interventional studies for regulatory review should take responsibility for all activities related to the design, conduct (including data analysis), and oversight of the studies. These activities should include, but not be limited to: − Selecting researchers qualified by training and experience to perform study-related activities and confirming that researchers have the skills and information needed to perform their roles in the study − Ensuring that the study is conducted following the final protocol and SAP and documenting any deviations − Maintaining and retaining adequate study records − Ensuring that FDA can access and verify relevant records (see section III.B.3 of this guidance for data access considerations) − Ensuring appropriate oversight of the study, including (when applicable) selecting a monitor qualified by training and experience.

This guidance is part of a series of guidances that the FDA has already published, or plans to publish, as part of the agency’s RWE program and in support of the 21st Century Cures Act and the Prescription Drug User Fee Act.


How PLG can support your RWD/RWE and other aspects of your Clinical and Non-Clinical Trials?

Conducting and managing Clinical Trials is never a straightforward process. There are subtle nuisances and complex regulations based on your product, the treated disease, the population’s reaction, the regulatory governing body, and many other factors. Many companies and their medicines being developed require an overarching and highly detailed objective analysis for the development and the market approach. Utilizing this premise, ProductLife Group has gathered Clinical and Non-Clinical experts with over forty years of experience in the industry. They have worked from simple generics to complex new chemical and biological entities. They have supported the management of Clinical Trials and attended Scientific Advice and Type C meetings with clients to gain clarification on development protocols. They are eager to take on new challenges, and your project will be the next successful case; whether you are conducting Decentralized Clinical Trials or utilized RWD/RWE information, consider PLG as your partner.


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Real-World Data (RWD) and Real-World Evidence (RWE) to Support Regulatory Decision-Making