06/04/2024

On May 6th, 2024 the US Food and Drug Administration (FDA) and the National Institute of Health (NIH) released a Request for Information regarding their recently developed draft: Glossary of Terms and Definitions. Innovations in the design and conduct of clinical trials, such as incorporating real-world data to generate real-world evidence, has led novel terms being used to describe these innovations. Many of these innovations including the use of artificial intelligence and new technologies for data exchange will be addressed in the upcoming Annex-2 of the ICH E6(R3) Guidelines for Good Clinical Practice (for more information on the new Annex please click here). However, there has not been a well-established consensus on what the definitions for these terms should be. As a consequence, the same terms have been used by different individuals involved in clinical studies to describe different concepts and thus resulting in inconsistency within the published results of clinical research. The FDA-NIH glossary is intended to create a shared understanding of the meaning of these novel terms to promote efficient and effective communication within clinical research.

The draft glossary is divided into 2 sections, the first is Terms for Comment, these are 37 terms that the FDA and NIH have isolated as being problematic when it comes to how they are currently being defined and used in the literature. The Terms for Comment include:

Causal Effect: A measure of difference in outcome that would be expected in individuals subjected to an exposure of interest compared to the expected outcome if those same individuals were subjected to specified alternative exposure (including no exposure).
- Source: Adapted from Musci R.J. & Stuart, E. (2019). Ensuring causal, not casual, inference. Prevention Science, 20, 452-456, https://doi.org/10.1007/s11121-018-0971-9.
Pragmatic Elements: Design features that can be integrated into a clinical trial, including but not limited to, one or more of the following elements: broad eligibility criteria, simplified recruitment and follow-up, flexibility in delivery of the intervention (e.g., community settings), flexibility in assessment frequency, and measurement of outcomes relevant to the population.
Umbrella Trial: Trial designed to evaluate multiple medical products in seperate sub-studies concurrently for a single disease or condition.
- Source: Adapted from FDA draft guidance Master Protocols for Drug and Biological Product Development (December 2023). When final, this guidance will represent FDA’s current thinking on these topics.

For a full list of the Terms for Comment and the proposed definitions along with the any source material the FDA and NIH used to develop these definitions, please click here.

The second section of the glossary is Terms for Reference. These are 8 terms that are not up for public commentary as their definitions are already well-established in the clinical research community. These terms are meant to provide context for the Terms for Comment, including:

Adaptive Design: A clinical trial design that allows for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial.
- Source: FDA final guidance Adaptive Design Clinical Trials for Drugs and Biologics Guidance for Industry (December 2019).
Basket Trial: Trial designed to evaluate a medical product for different diseases, conditions, or disease sub-types.
- Source: Adapted from FDA draft guidance Master Protocols for Drug and Biological Product Development (December 2023). When final, this guidance will represent FDA’s current thinking on these topics.
Observational Study, Prospective: A study in which the population of interest is identified at the start of the study, and exposure/treatment and outcome data are collected from that point forward. The start of the study is defined as the time the research protocol for the specific study question was initiated.
- Source: Framework for FDA’s Real-World Evidence Program (December 2018).

To see the full list of Terms for Reference, their definitions, and source material, please click here. Industry wide acceptance of the clearly defined terms could avert any miscommunication between clinical research stakeholders, thus upholding the rights and safety of clinical research participants. Terms for Reference can already be found in FDA publications. For example the ICH E8(R1) General Considerations for Clinical Studies Guidance for Industry uses terms such as; confounding, electronic health records, interventional and observational study and others in a manner that follows the definitions in the glossary (Clinical Pathways currently offers an overview course on ICH E8(R1) which can be found here).

For those who wish to provide commentary, including proposals for other pertinent terms that should also be included or if any should be removed, please click here to be brought to the NIH website and fill out the required fields as instructed on the page. The deadline for submitting comments is June 24, 2024.