FDA Lays Out Qualification Path for Biomarkers in Clinical Trials

December 17, 2018

The FDA last week set out a path for clinical researchers aiming to use biomarkers as a way to increase their trials’ timeliness and efficiency.

A new draft guidance, “Biomarker Qualification: Evidentiary Framework,” explains what steps researchers must take to prove to the agency that their proposed biomarkers are valid indicators of trial results.

That validation should take the form of a needs assessment, an explanation of the proposed biomarker’s context of use and a thorough risk/benefit analysis, the 16-page draft guidance says.

A needs assessment should describe “the current drug development landscape, such as the use and limitations of available biomarkers or other drug development tools, and the added value the novel biomarker could provide to the current drug development process.”

Context of use has two elements: the biomarker’s category and its proposed use in drug development. Researchers should focus on a single context for every proposed biomarker. The proposed use should lay out a biomarker’s purpose in drug development, the stage of drug development (a phase I clinical trial, for instance) in which the biomarker will factor, the clinical trial population or the model system and the therapeutic mechanism of action where the proposed biomarker would add value.

Researchers may not have enough information to describe a biomarker’s context of use, the agency acknowledges, because accumulating the data to support a biomarker “can take considerable time and resources.” In such cases, the FDA might be willing to qualify a biomarker with a limited contextual scope, “which could result in the accumulation of additional evidence that can help qualify the biomarker … with a more expanded scope in the future,” Tuesday’s draft guidance states.

Regarding the risk/benefit analysis of a proposed biomarker, the draft guidance advises trial sponsors to “address the consequences of incorrect decisionmaking or harm to patients if the correlation between the biomarker and the outcome of interest does not indicate what it is intended to indicate.”

Sponsors should answer four key questions in their risk/benefit analysis:

  1. Can the biomarker add value to drug development?
  2. What other tools are available for the biomarker’s proposed use and what added value might the biomarker provide?
  3. What are the anticipated consequences if the biomarker is unsuitable for its proposed use?
  4. What factors or other tools can mitigate the potential risks of relying on the biomarker for its proposed use if the biomarker does not perform as expected?

Regulators are more likely to tolerate uncertainty if sponsors can show that the benefits of a proposed biomarker far outweigh the risks or if they can demonstrate that they’ve got an effective risk mitigation plan in place.

Any biomarker will need a reliable test for its validity, and both analytical and clinical validations can help demonstrate the marker’s context, the FDA says. Any biomarker test will have to “be robust, sensitive and specific enough to support the decisions” defined by the context of use.

“Well-validated biomarkers confer additional confidence in regulatory decisionmaking and, as such, often bring efficiencies to clinical trials,” says Jonathan Seltzer, president and CEO of WCG ACI Clinical, a clinical services organization specializing in endpoint adjudication and safety assessment.

“I hope the draft guidance encourages more sponsors to think about developing biomarkers [that] support their clinical endpoints,” Seltzer says, adding that biomarkers have proven especially valuable in the oncology and clinical care arenas.

The new draft guidance is important for two reasons, says James O’Reilly, a professor of public health at the University of Cincinnati’s medical school. The first is that it lays down more-or-less objective conditions for drug sponsors, which means that the public can rest more assured that drugs are coming to market because of sound science rather than effective lobbying.

The second reason, according to O’Reilly, is that “it levels the playing fields” for drug sponsors, especially foreign drug companies. Once a biomarker is established, theoretically, everyone will be able to use it for trials, he says.

“This will be a big deal in allowing multiple, competing companies to set the measurement for getting their product onto the market ,” O’Reilly tells CenterWatch. “It’s not a free ride, it’s not how persuasive or how friendly Ms. Smith was to reviewer Jones, it’s how effective the company is in demonstrating that this is the right biomarker, it’s properly qualified, it’s suitable, and it’s streamlined drug development for everybody.”

The draft guidance offers an opportunity for drug sponsors to start “building a ladder” for proposed biomarkers, he adds.

“Get your teams together now to think about what biomarkers you’ll want to use over the next several years and get your letters of intent working and think about your qualification plan as part of your product development,” he says.

Any comments on Tuesday’s draft guidance are due by Feb. 9.

Read the draft guidance here: 


-By Bill Myers