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EXRNA AS CLINACAL BIOMARKERS
In order to develop exRNAs as clinical biomarkers, the development process has to go through rigorous
steps to define the intended target, examine clinical utility (must inform and guide patient treatment,
management, and outcomes) and, validate the test both analytically (ensures specificity, accuracy, precision,
and other characteristics of a biomarker test or device) and clinically (ensures that the test or device
performs as intended) before clinical application. Since the U.S. Food and Drug Administration (FDA) is
the regulatory body to qualify biomarkers for intended clinical studies, it is therefore relevant to understand
the FDA definition of a biomarker and review various resources available for investigators.

FDA’s definition of a biomarker
The FDA defines a biomarker as a defined characteristic that is measured as an indicator of normal
biological processes, pathogenic processes, or responses to an exposure or intervention, including
therapeutic interventions [46,47] . Qualified biomarkers have the potential to provide valuable information that
may reduce uncertainty in regulatory decisions during drug development. When a biomarker is qualified,
it means that it has undergone a formal regulatory process to ensure that it is reliable and reproducible for
a specific interpretation and application in medical product development and regulatory review, within the
stated context of use.

FDA BEST biomarker categories resource
It is essential to have effective, unambiguous communication for efficient translation of promising scientific
discoveries into approved medical products. Unclear definitions and inconsistent use of key terms can
hinder the evaluation and interpretation of scientific evidence and may pose significant obstacles to
medical product development programs.

The FDA-NIH Joint Leadership Council identified harmonization of terms used in translational science
and medical product development as a priority need, with a focus on terms related to study endpoints and
biomarkers. Working together with the goals of improving communication, aligning expectations, and
improving scientific understanding, the FDA and NIH developed the BEST (Biomarkers, EndpointS, and
[46]
other Tools) resource for biomarker researchers . BEST defines seven biomarker categories: susceptibility/
risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, and safety. The BEST
glossary aims to capture distinctions between biomarkers and clinical assessments and describes their
distinct roles in biomedical research, clinical practice, and medical product development.

FDA center for drug evaluation and research biomarker qualification program
The mission of this program is to work with external stakeholders to develop biomarkers as drug
development tools. Qualified biomarkers have the potential to advance public health by encouraging
efficiencies and innovation in drug development. The goals of the biomarker qualification program (BQP)
are to (1) support outreach to stakeholders for the identification and development of new biomarkers; (2)
provide a framework for the review of biomarkers for use in regulatory decision-making; and (3) qualify
biomarkers for specific contexts of use that address specified drug development needs.

Biomarker qualification is a process involving three stages that provide increasing levels of detail for the
development of a biomarker for its proposed context of use. The processes to complete submissions to the
center for drug evaluation and research (CDER) BQP are (1) a letter of intent (LOI); (2) qualification plan;
and (3) full qualification package. More information about the FDA CDER BQP can be found on their
[47]
website . A Pre-LOI meeting can be helpful for requesters to receive guidance from the FDA regarding
[48]
their biomarker programs before submission to the program . Once a biomarker is qualified it can then
be used in multiple drug development programs for the context of use without FDA re-review.