The development of biomarkers for Alzheimer’s and other neurodegenerative diseases is accelerating rapidly, with blood tests and new fluid and imaging markers on the horizon (Aug 2018 news; Nov 2018 news; Dec 2018 news). However, developers must contend with an uncertain process for validating such biomarkers for clinical trials. To remove some of the mystery, the FDA issued a draft report last month that lays out a framework for biomarker qualification. The culmination of public workshops and recommendations from numerous stakeholders, including the National Institutes of Health, industry, academia, and patient groups, the report remains open for comment until February 11. After considering responses, the FDA will issue a final guidance. 

Validation. The interrelated processes of analytical and clinical validation of the biomarker for its proposed context of use (COU).

Researchers, clinicians, and others are encouraged to comment at It is unclear if the partial U.S. government shutdown might affect this website or the deadline. Comments can also be sent via old-fashioned snail mail to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rooim 1061, Rockville, MD 20852.

In the draft, the FDA describes the types of evidence the agency will consider during the biomarker qualification process. Firstly, developers must clearly describe the intended use of the biomarker, make the case that it is needed, and explain any potential risks posed to patients. Beyond that, they must provide data supporting the relationship between the biomarker and the clinical outcome it is supposed to reflect, and demonstrate that the biomarker can be reproducibly and accurately measured. The two provisions are distinct, yet indelibly intertwined, according to the agency:

“Clinical validation and analytical validation are distinct processes; however, the two processes are iterative and dependent on one another. A reliable test should be used to measure the biomarker before the biomarker measurement can be established, and the cutoffs should be defined before the biomarker test can be analytically validated. Through this iterative process, experience with the biomarker and the biomarker test could lead to improvements in the technical performance of the test and the understanding of the biomarker’s biological and clinical significance.”

The FDA emphasized that the final guidance will not necessarily be binding. Ultimately, each biomarker submission will be considered on its own merits.—Jessica Shugart


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News Citations

  1. Blood Test for Neurofilament Light Chain Kicks Up Biomarker Research
  2. Blood Tests for Amyloid Step Out at CTAD
  3. Could a Blood Test for Tau Diagnose Alzheimer’s Disease?

External Citations

  1. draft report

Further Reading