Biomarkers for Alzheimer’s Disease: Context of Use, Qualification, and Roadmap for Clinical Implementation

Abstract

Background and Objectives: The US Food and Drug Administration (FDA) defines a biomarker as a characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention. Biomarkers may be used in clinical care or as drug development tools (DDTs) in clinical trials. The goal of this review and perspective is to provide insight into the regulatory guidance for the use of biomarkers in clinical trials and clinical care. Materials and Methods: We reviewed FDA guidances relevant to biomarker use in clinical trials and their transition to use in clinical care. We identified instructive examples of these biomarkers in Alzheimer’s disease (AD) drug development and their application in clinical practice. Results: For use in clinical trials, biomarkers must have a defined context of use (COU) as a risk/susceptibility, diagnostic, monitoring, predictive, prognostic, pharmacodynamic, or safety biomarker. A four-stage process defines the pathway to establish the regulatory acceptance of the COU for a biomarker including submission of a letter of intent, description of the qualification plan, submission of a full qualification package, and acceptance through a qualification recommendation. Biomarkers used in clinical care may be companion biomarkers, in vitro diagnostic devices (IVDs), or laboratory developed tests (LDTs). A five-phase biomarker development process has been proposed to structure the biomarker development process. Conclusions: Biomarkers are increasingly important in drug development and clinical care. Adherence to regulatory guidance for biomarkers used in clinical trials and patient care is required to advance these important drug development and clinical tools.

Alzheimer's disease drug development pipeline: 2023

“…Tau PET is used as an outcome in six Phase 2 trials and nine Phase 3 trials. Biomarkers are playing an increasingly large role in clinical trials in which they may have one or more defined contexts of use including risk determination, diagnosis,monitoring, pharmacodynamic measurement, prognosis determination, response prediction, and safety 14,15. Use of markers in drug development increases the probability of success and is increasingly viewed as a foundational aspect of clinical trials of DMTs 16.…”

The potential clinical value of plasma biomarkers in Alzheimer's disease

“…19 They are valuable tools for gathering real-world evidence on a particular biomarker or disease, supporting product development, and conducting non-clinical laboratory research, but they must not be used for clinical decision making or diagnosis and must be labeled as "for research use only." 18,19 LDTs are designed, manufactured, and used in a single laboratory or laboratory network 18,40 and are important for accelerating research progress as they can often be developed more quickly and cheaply than IVDs because they only undergo limited analytical and clinical validation and regulatory review. 40,41 They can also be modified to allow for the rapid incorporation of new findings.…”

“… Note : Table created using information from references Cummings and Kinney, 18 U.S. Food & Drug Administration, 19 and Teunissen et al 20 …”

“…Such tests could add clinical value by potentially streamlining diagnosis, improving the patient journey, and alleviating pressure on health‐care systems. There are a range of plasma biomarker tests at different stages of development for use in AD research and as part of the AD diagnostic pathway and care continuum, including in vitro diagnostic devices (or tests; IVDs), laboratory‐developed tests (LDTs; also known as in‐house devices), and research use only devices (or tests; RUOs) 18 . As IVDs, LDTs, and RUOs have different intended uses and are subject to different regulatory requirements, understanding the differences among them is vital so that they can be appropriately implemented into the AD diagnostic pathway and care continuum.…”

Biomarkers for clinical use in psychiatry: where are we and will we ever get there?

“…For exa mple, before the discovery of biomarkers, Alzheimer's disease (AD) diagnosis was primarily based on the clinical symptom profile, as the definitive diagnosis required post-mortem brain pathology. The diagnostic process was transformed with the discovery of imaging and cerebrospinal fluid biomarkers which can now be used to confirm the diagnosis of AD in living humans 1 .…”