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The American agency Food and Drug Administration (FDA) innovated once again by creating a new guide on real-world evidence (RWE) and real-world data (RWD) to support drug approval.

The guide begins by defining exactly what real-world evidence and real-world data are, as outlined below:

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Real World Evidence (RWE) – is clinical evidence based on the usage and potential benefits or risks of a medical product derived from RWD analysis.

Real World Data (RWD) – are data relating to the patient's health status and/or the delivery of healthcare, which is routinely collected from a variety of sources.

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The guide continues by presenting two important definitions that aim to establish distinctions between the interventional study and the non-interventional study, as explained below:

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Interventional study (clinical trial) – is a study in which participants, healthy volunteers or volunteers with the condition or disease under study, are assigned to one or more interventions, in accordance with a study protocol, in order to evaluate the effects of those interventions on subsequent results related to their health. As an example, the guide defines a traditional randomized clinical trial, in which some participants are randomly assigned to receive a drug of interest, while others receive an active comparator drug or placebo.

Non-interventional study (observational study) – is a 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. The guide defines as an example observational cohort studies, in which patients are identified as belonging to a study group according to the drug(s). Therefore, for the FDA, non-interventional studies are not considered clinical investigations and, therefore, do not require an investigational new drug application.

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If companies hire third parties to perform certain study-related tasks, they must document the roles and responsibilities of the third party performing the tasks. These documents must be made available to FDA upon request. Companies must remain responsible for all study-related activities unless a company has transferred its responsibility to a contract research organization.

The FDA expects the company to retain and make available to the agency, upon request, a log of any researcher or researchers who have significant involvement in the design or conduct of the study. The log must contain information about the researchers, including:

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1. Researcher's name and affiliations

2. Description of functions or activities performed

3. Qualifications relating to education, training, and experience to perform the proposed work and

study function

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1.1.                    NON-INTERVENTIONAL STUDIES

The FDA makes clear that although many non-interventional studies involve only the analysis of data reflecting the use of a marketed drug in routine medical practice, certain non-interventional studies include protocol-specified activities or procedures, such as, for example, questionnaires, laboratory tests, imaging studies, etc., which collect additional data to help resolve questions of interest in these studies. However, the protection of human subjects in such circumstances is of critical importance. Various sources of RWD can be analyzed in non-interventional studies, including electronic health records (EHR) and medical statements.

To adequately assess the results of a non-interventional study that supports a marketing application, the FDA must be confident, based on corresponding documentation, that specific data sources or databases were not selected, or that specific analyses were not conducted to favor a certain conclusion. Companies must describe, in the study protocol or as an annex to the protocol, the data sources accessed during study design, including results from feasibility evaluations or exploratory analyses of these data sources, as well as describe how the choice of final data sources, study design elements, and analytical approaches align with the research question of interest and confirm that data sources, study design elements, and analytical approaches were not selected to favor specific study results. To ensure transparency, companies must publish their study protocols on a publicly available website.

Companies must describe patient characteristics from the source population (i.e., the population from which the study population is drawn) and the study population (i.e., the population for which analyses are conducted) in their final report, as well as observing any differences that could impact the study's final results. Additionally, they must document the analyses performed on the final data set or data sets in accordance with the statistical analysis plan; any additional analyses should be described as exploratory.

Companies wishing to use a non-interventional study to support the commercialization of a product must ensure that they are able to submit patient data for any RWD that was analyzed as part of the clinical study included in a marketing registration application. Further, it must be ensured that the RWD, programming codes, and associated algorithms submitted to the FDA are documented, well annotated and complete, which allows the FDA to replicate the study analysis using the same data set and analytical approach.

Likewise, companies that submit non-interventional studies for regulatory review must be responsible for all activities related to the design, conduct, and analysis of data, as well as oversight of the studies. These activities must include, but are not limited to:

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1. Selecting researchers qualified by training and experience to perform study-related activities and confirming that researchers have the necessary skills and information to perform their roles in the study;

2. Ensuring that the study is conducted in accordance with the final protocol and statistical analysis plan, and documenting any deviations;

3. Maintaining and retaining adequate study records;

4. Ensuring that FDA can access and verify relevant records; and

5. Ensuring appropriate supervision of the study, including (when applicable) selecting a monitor qualified by training and experience.

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1.2.                  INTERVENTIONAL STUDIES

The FDA recognizes the potential utility of using RWD in interventional studies, such as, for example, to identify potential participants for a randomized, controlled study trial, to ascertain endpoints or outcomes, such as the occurrence of stroke or other discrete events, serious illnesses, hospitalization, survival, etc., or even to serve as a comparator arm in an externally controlled trial, including historically controlled trials.

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1.3.                   CLINICAL STUDY OVERSIGHT

Clinical study oversight is one of the key quality control activities critical to ensuring that: (1) the study is conducted in accordance with the protocol, (2) data submitted to the FDA is reliable, and (3) data is adequately protected. The FDA encourages companies to use a risk-based quality management approach to undertake oversight.

For non-interventional studies, oversight should begin with extracting data from RWD sources and focusing on protecting human subjects, as applicable, and maintaining data integrity.

As part of oversight of a non-interventional study, companies must, at a minimum:

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1. Ensure that the RWD required by the protocol are accurate and consistent with the source records;

2. Ensure that pre-specified plans (e.g., the statistical analysis plan), protocol, and study procedures (e.g., for curation, transformation, and reporting of results) were followed;

3. Ensure that deviations from pre-specified plans and study protocols and procedures are identified and documented and, when necessary, promptly assessed and solved according to the significance of the identified deviations.

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1.4.                  SAFETY REPORTING

Non-interventional studies examine the use of a drug in routine medical practice, and the FDA requires applicants to comply with postmarketing safety reporting regulations regarding the occurrence of relevant adverse events.

If a company identifies adverse events that are subject to postmarketing reporting requirements while conducting a non-interventional study, such events must be reported in accordance with applicable postmarketing reporting requirements.