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Koneksa at FDA Public Meeting on Multi-Component Biomarkers with CMO John Wagner

Multi-component biomarkers: what are they, and why does it matter?

While they are increasingly common in medicine – especially in drug development – there are no “official” definitions yet of multi-component biomarkers, and this can cause confusion.

And so, on March 23-24 2022 (rescheduled from March 2020), the FDA convened a public meeting: a workshop, led by their Biomarker Working Group, in which experts gathered to present the issue, discuss possible solutions, and hear public comment.

Koneksa CMO Dr. John Wagner presented the keynote address: “Promise, Practice, and Perspective on Terminology”, and was accompanied by leaders from the NIH, FDA, and institutions worldwide. John’s presentation provided an overview of the issue and offered definitions for consideration; others spoke on efforts like the “Biomarkers, EndpointS, and other Tools” (BEST) Resource, a living glossary that is a collaboration between NIH and FDA; regulatory perspective; test evaluations; and case studies.

A brief summary follows of some of the main issues addressed by John and his colleagues. (The full presentations can be viewed on the FDA website and are highly recommended!)

What Is a Biomarker, Anyway?

The BEST Resource defines a biomarker as: “a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic interventions.” Biomarkers may include molecular, histologic, radiographic, or physiologic characteristics; but they are not clinical endpoints, which are measures of how an individual feels, functions, or survives.

What’s the Problem?

John highlighted the “multi-component biomarker tower of Babel,” pointing out that while a PubMed search will show 130 results for “multi-component biomarker,” there are also 91 for “multiplex biomarker,” 46 for “integrative biomarker,” and 34 for “multimodal biomarker.” This demonstrates two things. First, many different terms are being used (these are just a few out of many). Second, there are presently relatively few citations overall, compared to the term “biomarker” clocking in at over 1,000,000 citations, which shows the potential for greater use.

Why Does this Matter So Much?

The efficiency of surrogate endpoints (biomarkers that have achieved credentials confirming they can substitute for clinical endpoints) is associated with higher numbers of new drugs for patients. But inconsistent definitions around biomarkers and multi-component biomarkers have already caused misinterpretations, misunderstandings, errors, and failures. It can be difficult to make progress when you aren’t quite sure if everyone involved is using the same words to mean the same things – and that’s where our industry finds itself at present.

Four Proposed Definitions for Biomarkers & Their Sub-Types

Multi-component Biomarker: Biomarkers that can be used individually for pattern recognition, or can be used for a single calculated value derived from a defined set of biomarkers using a known algorithm; and which are required when the characteristic to be measured is not adequately captured by a single measurement.

Integrative Biomarker: A single calculated value derived from a set of biomarkers and a known algorithm. (Composite endpoints have been used for decades throughout medicine – for example, the HDL/LDL cholesterol ratio – and their methodology demonstrate how integrative biomarkers can be used.)

Multiplex Biomarker: Multiple single biomarkers that can be used individually in a panel, or for pattern recognitions. (An example of a multiplex biomarker are the vital signs we’re accustomed to having taken in a checkup or hospitalization.)

Classification Biomarker: Multiple biomarkers and a defined algorithm used to create an interpretation or categorization. (These may also be thought of as subtype of integrative or multiplex biomarkers, a combination of both of them, or as a completely separate category. An example of their use can be found in the way next-generation sequencing is used to identify patients that should use certain targeted therapies.)

Informed & Aligned
The speakers also explained the types of validation and qualification that are used to ensure that a biomarker is acceptable and used appropriately in a specific situation, and discussed several of the issues that are unique to multi-component biomarkers, and that will need to be addressed in defining them (and related terms).

The speakers also explained the types of validation and qualification that are used to ensure that a biomarker is acceptable and used appropriately in a specific situation, and discussed several of the issues that are unique to multi-component biomarkers, and will need to be addressed in defining them (and related terms).

This public meeting is the first step in a collaborative dialogue to work with the FDA, the NIH, and other experts in our industry to develop these terms and definitions to help better synchronize our industry’s efforts and improve this increasingly important aspect of drug development

Watch the webinar here and get in touch with Koneksa to learn more about our contributions to the healthcare industry and our work with digital biomarkers. Watch the webinar here and

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