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What is the FDA’s Biomarker Qualification Process?

May 26, 2016 | Jacquie Powell, PhD, Clinical Research Scientist II | Regulatory Affairs, Drug Development Consulting

Similar to Clinical Outcomes Assessments (COAs), biomarkers also have a qualification program that was developed by the Center for Drug Evaluation and Research (CDER) as one of the Drug Development Tools (DDT) Qualification Programs.

scopeJust like our previous post on the COA Qualification Program, this post discusses the Biomarker Qualification Program from a drug-development point of view.

What is a biomarker?

A biomarker is a measurable indicator used to assess: (1) a normal biologic process, (2) a pathogenic process, or (3) a response to an intervention or exposure.

One important thing to keep in mind is that, unlike COAs, biomarkers do not assess how individuals feel, function, or survive in their daily lives. As such, biomarkers are less subjective than COAs.

How many types of biomarkers are there?

Examples of different types of biomarkers are provided in a glossary that is part of the Biomarkers, EndpointS, and other Tools (BEST) Resource, which is currently under joint development by the FDA and the NIH. General definitions and examples of different kinds of biomarkers are provided below.

  • Susceptibility/risk biomarkers – Used to evaluate an individual’s potential for developing a disease or for assessing their sensitivity to different types of exposure. These types of biomarkers are particularly useful for individuals who don’t have a clinically apparent disease but may be susceptible.
    Example: Breast cancer genes 1 and 2 (BRCA1/2) mutations may be used as a susceptibility/risk biomarker to identify individuals who are predisposed to develop breast cancer.
  • Diagnostic biomarker – Used to identify individuals who are afflicted with a disease or condition and can also be used to define a subset of patients who may have a particular form of a disease.
    Example: Sweat chloride levels may be used as a diagnostic biomarker to confirm cystic fibrosis.
  • Monitoring biomarker – Used over time to detect a change in the degree or extent of a disease. These types of biomarkers may also be used to indicate toxicity, assess safety, or provide evidence of exposure (including exposure to medicinal products).
    Example: Prostate-specific antigen (PSA) may be used as a monitoring biomarker when assessing patients with prostate cancer to evaluate disease status or burden.
  • Prognostic biomarker – Used to identify the likelihood of a downstream clinical event such as disease recurrence, disease progression, or death.
    Example: C-reactive protein (CRP) levels may be used as a prognostic biomarker to identify adult patients with a greater liklihood of coronary artery disease.
  • Predictive biomarker – Used to identify individuals who are likely to respond either favorably or unfavorably to a specific medical intervention.
    Example: The presence of anti-drug antibodies (ADAs) may be used as a predictive biomarker to assess how an individual will respond to a particular medication over time.
  • Pharmacodynamic/response biomarkers – Used to show that a biological response has occurred in an individual who has received a medical intervention or medicinal product.
    Example: Hemoglobin A1c (HbA1c) may be used as a pharmacodynamic/response biomarker when evaluating patients with diabetes to assess response to antihyperglycemic agents or lifestyle changes.
  • Safety biomarker – Used to indicate the presence or extent of toxicity in an individual who has received a medical intervention or medicinal product.
    Example: Corrected QT interval (QTc) may be used as a safety biomarker to assess the potential for drugs to induce Torsades de Pointes.

chartBiomarkers provide valuable information throughout the drug-development process by providing data to inform drug-development decisions. The use of biomarkers can potentially reduce the time required to complete clinical trials, decrease the sample size needed to achieve statistical significance, and provide more clarity to the regulatory decision making process.

How do biomarkers get qualified?

Similar to the COA qualification process discussed in our previous post, biomarkers can also be qualified by the FDA so that they can be used by drug developers without the need to re-evaluate their validity. However, the use of biomarkers in any drug-development program should be carefully considered in consultation with the FDA.

The FDA’s biomarker qualification process is broken down into three sequential stages, and progression through these stages is contingent on positive feedback from the FDA:

  • Initiation stage – Submit a letter of intent (LOI) that includes a high-level description supporting the use of a biomarker within a proposed context of use (COU) to the FDA.
  • Consultation and advice stage – Put together a comprehensive biomarker qualification briefing package and receive input from the FDA.
  • Review stage – Submit a full qualification package to the FDA.

A checklist outlining the FDA requirements at each stage of biomarker development is provided in the Biomarker Qualification Submissions Checklist and biomarker qualification templates and examples are provided here. Also, the FDA recently released a guidance on the use of histopathology and its associated methodologies to support biomarker qualification.

A detailed description of the FDA’s biomarker qualification process is available as webinar slides here.

What happens once a biomarker is qualified?

Once a biomarker is qualified, the FDA will send a letter to submitter(s) informing them of their decision. If the biomarker is qualified, it will then be posted on the DDT public webpage for potential use in other drug‑development programs. Similar to COAs, once a biomarker is validated, it does not need to be re‑evaluated for use within a specific COU. However, this does not mean that the FDA will necessarily accept these biomarkers in every clinical development program that cites the same COU; even though a biomarker is qualified, its inclusion in a drug-development program should be carefully considered in consultation with the FDA.

Let us know what you think

Are you thinking of developing or using a pre-existing biomarker in your clinical development program? IMPACT has experienced regulatory affairs professionals ready to consult with you. If you would like to discuss your specific needs, please contact us or give IMPACT a call today at (919) 899-9248.

Sharing images courtesy of Serge Bertasius Photography and Becris, respectively, from

Category: Regulatory Affairs, Drug Development Consulting
Keywords: Biomarker qualification, FDA, Drug Development Tools Qualification Programs, CDER

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