Industry groups and drugmakers are seeking further clarity from the US Food and Drug Administration (FDA) on draft guidance related to the qualification of biomarkers.
The draft from last December
, which FDA emphasizes is a first draft, comes as FDA has qualified eight biomarkers
and received 29 submissions
. The draft notes that progress in biomarker qualification has been stymied by the lack of a clear, predictable and specific regulatory framework that lays out the type and level of evidence to support regulatory decision making.
The need for such a framework is outlined in the comments on the draft.
For instance, industry group BIO, while calling for some flexibility in the context of rare diseases, also requests that FDA consider including information in the guidance pertaining to the qualification of a biomarker that already has an established specific context of use (COU).
“For example, it would be helpful for the FDA to include information regarding whether a Sponsor can build upon a specific COU or whether a separate biomarker qualification submission would be required. Additionally, a single biomarker may serve multiple utilities. For example, pre-treatment levels of a biomarker may be predictive of response to a treatment and the same biomarker may also provide insights regarding treatment efficacy. To this end, we ask the FDA to clarify as to whether each proposed biomarker utility would require its own specific COU and a separate qualification submission,” BIO’s Danielle Friend, director of science and regulatory affairs, writes.
Similarly, Novo Nordisk encourages FDA to offer a more detailed description on the process of determining the COU for a biomarker with multiple applications.
“It is unclear how this categorization would work over time, and the lack of clarity could be limiting for biomarker development. For example, a biomarker may be initially identified and qualified for one category of use and the COU defined based on that initial qualification. However, over time, a biomarker may prove useful and be qualified for other categories of use,” Novo Nordisk’s VP of regulatory affairs Robert Clark writes.
“We believe FDA needs to build in greater flexibility for qualification of biomarkers in multiple categories, both simultaneously and over time, and permit modification of COU for biomarker qualification as research and investigations continue over time,” he adds.
Novartis, meanwhile, explains how it would also be useful for FDA to share how sponsors approached and used the biomarker guidance to achieve successful qualification.
“Given the rapid increase in use of machine learning/A.I. in biomedical science, it would also be useful for FDA to share thoughts on how these new technologies might contribute to biomarker qualification when there may not be clear biological rationale for each marker that is part of such algorithms and where the markers may span multiple modalities,” Novartis’ Chin Koerner writes.
And the nonprofit International Consortium for Innovation and Quality in Pharmaceutical Development took issue with the fact that although the qualification of a number of biomarkers has been occurred, the use of those biomarkers has been hampered by lack of regulatory guidance on how to use them.
“One example is fecal calprotectin, which is generally considered as a robust surrogate biomarker for mucosal inflammation in inflammatory bowel disease patients. Several qualified, quantitative assays are available but they have different cut-off values indicative of mucosal inflammation. Therefore, even though a biomarker is well-accepted to perform as intended (which is the purpose of this document), a lack of harmonization of different qualified assays and standardization of data interpretation remains a road block to the use those biomarkers in clinic and in drug development. In most cases, those biomarkers are positioned as ‘exploratory biomarkers’ in drug development programs and undermine the full potential of those biomarkers,” the consortium writes.