The FDA released a Draft Guidance in December (2018) on the evidentiary framework and standards required to achieve qualified biomarkers. It is intended to cover a regulatory gap related to the use of biomarkers outside of specific drug programs. As such, this Draft Guidance supports the Qualification of Drug Development Tools section (507) of the 21st Century Cures Act enacted on December 13, 2016 and provides the framework for developing the data set (evidence) supporting designation of a biomarker as qualified for a particular context of use (COU). Within this context of use, the qualified biomarker, “…can be relied on to have a specific interpretation and application in drug development and regulatory review…” While biomarkers measured by medical devices are outside the scope of the Draft Guidance, the Agency broadens the practical scope beyond qualified biomarkers to include the evidence needed to support the use of biomarkers in INDs, NDAs and BLAs:
“Many principles discussed in this guidance could also be appropriate when considering the evidence scientifically sufficient to support the use of a biomarker in an individual drug development program (e.g., investigational new drug application, new drug application, or biologics license application submissions).”
This extension, and the language present in the latter part of the document, aligns well with last year’s FDA Final Guidance for Industry on Bioanalytical Method Validation (BMV) that for the first time brought biomarkers measured by Ligand Binding Assays (LBA) and mass spectrometry into a regulated context.
The evidentiary framework is intended to define the type and extent of evidence required to support the qualification of the biomarker. Listed are four specific areas that must be addressed:
(1) describing the drug development need,
(2) defining the COU,
(3) considering potential benefits if the biomarker is qualified for use, and
(4) considering potential risks associated with the proposed use of the biomarker in a drug development program
The Draft Guidance addresses each of these in some detail but is not overly rigid or prescriptive in its requirements, in recognition that the vast breadth of biomarkers and their use in drug development cannot be comprehensively addressed in detail. By using the prior definitions of the FDA-NIH BEST classification of biomarkers (diagnostic biomarker, monitoring biomarker, pharmacodynamic/response biomarker, predictive biomarker, prognostic biomarker, safety biomarker, susceptibility/risk biomarker), the Draft Guidance minimizes potential inconsistencies and confusion arising from the creation of a different set of terminology. The Draft Guidance also distinguishes the analytical validation (assay performance characteristics) from the clinical validation (correlation of the biomarker and outcome of interest).
A significant section of the document relates to the “Analytical Considerations” for the test used to measure the biomarker. Here, the language is similar to the BMV in that the assays should be “robust, sensitive, and specific enough to support the decisions defined by the COU”, whereas the BMV lists six assay characteristics (accuracy, precision, selectivity, sensitivity, reproducibility and stability). Interestingly, the Draft Guidance proposes that the assay is a 3-part system for obtaining results comprised of the source or materials for the assay, the assay itself and how the results will be interpreted. This overarching approach ensures that not only is the assay considered within the validation, but also that the sample collection, transport and storage of the samples are essential components of the process and not only must be considered, but defined in order to obtain a reliable measurement. The last item, interpretation, places the measured results within the spectrum of disease and healthy patients to ensure proper utilization of the measurements and is consistent with clinical chemistry practices for normal and disease state ranges. With regard to the actual assay, issues defined in more detail within the BMV (e.g., reagent lots, procedures) ensure that adequate documentation is present and support risk-assessments when future changes to an assay are made. Along with the four components of the evidentiary framework mentioned above, the Draft Guidance recommends that during the process to specify the assay criteria (e.g., range, precision), three other factors be considered:
(1) The performance characteristics of existing measurement methods
(2) The biological variability of the biomarker in the populations of interest, if known
(3) The minimum magnitude of biomarker change expected to affect decisions for the proposed COU (i.e., cutoff for separating populations or determining change from baseline)
These factors have been extensively discussed by the LBA and mass spectrometry bioanalytical communities supporting drug development.
Furthermore, while the FDA Guidance on Histopathology (Considerations for Use of Histopathology and Its Associated Methodologies to Support Biomarker Qualification) is referenced, the BMV is not. Since the Draft Guidance focuses on the development of qualified biomarkers, omission of the BMV reference may be perceived as either the Agency not wanting to constrict practices or leaving open the option to adding it during the revision process. In the future Final Guidance, it would be beneficial to the medical and pharmaceutical industry to include or specifically exclude the BMV, especially since the background portion of the document makes reference to the considerations of the Draft Guidance as applicable to drug development in practice.
Overall, the Draft Guidance does not change current practices for LBA and LC-MS practitioners in drug development. It does, as intended, provide additional regulatory clarity on Agency expectations.