FDA, NIH Unveil Initial Framework for Biomarker Qualification

Regulatory NewsRegulatory News | 12 December 2016 |  By 

Officials from the US Food and Drug Administration (FDA), the Foundation for the National Institutes of Health (NIH) and other stakeholders, including experts from Genentech, Merck, Pfizer and Takeda, have released a framework for proposed evidentiary criteria to support the regulatory acceptance of biomarker use in drug development programs.

The framework, released 6 December, is expected to help support FDA in the development of relevant guidance(s) for evidentiary criteria (EC) in biomarker qualification.

“Since each category of biomarker and [context of use] COU has unique factors to consider as part of the development process, it is proposed that modules be created to address these more specific issues. The second part of this document specifically focuses on the first such 'module,' describing evidentiary considerations in the qualification of biomarkers used in determinations of clinical drug safety assessments. These considerations are further tested and illustrated in three accompanying case studies of markers that have been or could be proposed for use in drug safety assessments,” the Biomarkers Consortium Evidentiary Standards Writing Group said in the report.

The group said it expects such an EC framework will benefit the biomarker qualification process in two ways: By providing biomarker developers and FDA with increased clarity, predictability and consistency across biomarker development programs, and by increasing the quality of biomarker qualification submissions and their reviews by offering specifics on the level of evidence required to support a COU.

"It’s hard to overestimate the potential impact of the work that is being done here,” Janet Woodcock, director of FDA’s Center of Drug Evaluation and Research, said about the effort during her keynote address at an April 2016 workshop on the topic.

The 21st Century Cures bill, which is expected to be signed by President Barack Obama on Tuesday, also establishes a review pathway at FDA for such biomarkers and other tools that can be used to help shorten drug development times, aiming to help reduce the high failure rate.

General EC Framework Components  

The general framework is built on five components:

1) Describing the drug development need

2) Defining the COU (i.e., how the biomarker will be used in a drug development context)

3) Considering the potential benefits should the biomarker project be successful (e.g., improved sensitivity or selectivity)

4) Considering the risks associated with the intended use of the biomarker in a drug development program (i.e., frequency and consequence of false negatives or false positives)

5) Determining the EC to support the COU based on the benefits and risks  

“The submitter is expected to provide a clear and objective explanation of the anticipated benefits, the reasonable risks, and the risk mitigation strategies proposed for use of the biomarker within the proposed COU,” the framework says. 

Individual Components of the EC Framework

Companies will have to provide a “need statement,” which is a concise description of the knowledge gap or drug development need (e.g., improved safety monitoring) that the program is planning to address.  

“Generally speaking, we need reliable biomarkers that can reduce uncertainty and support decision making in the drug development process. The level of this need, however, will vary based on the current landscape, such as the reliability of currently used biomarkers and the level of improvement new biomarkers might provide to the patients and drug development process,” the framework adds.

As far as the COU, the framework calls for a statement that fully describes the way the medical product development tool is to be used and the medical product development‐related purpose of the use.

“The COU is critical for the biomarker qualification submission and is based in large part of on the need statement that the biomarker is intended to address,” the framework says, noting that FDA has identified considerations related to a biomarker’s COU, including the concise use statement and the comprehensive description of conditions for use in the qualified setting.

Back in September, FDA sought comment on the utility of a list of examples of biomarkers used as outcomes.

And in terms of the relationship between benefits and risks in the regulatory context, the framework lays out three potential areas of interest: 1) the ability of a clinical trial to yield interpretable results, 2) the impact on patients enrolled in a clinical trial, and 3) the impact on patients from a public health perspective should a product be approved or denied because, in full or in part, of biomarker data.

In addition to the outline of this framework, the group says it is developing future framework documents on analytical validation and statistical considerations.

Framework for Defining Evidentiary Criteria for Biomarker Qualification: Final Version


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