Biomarker Validity And Validation The Regulatory Perspective

The FDA's Guidance for Industry: Pharmacogenomic Data Submission, published in 2005, has helped introduce and define exploratory and valid biomark-ers. The FDA defines a valid pharmacogenomic biomarker as one that is measured in an analytical test system with well-established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the toxicological, pharmacological, or clinical significance of the test result. The FDA further classifies valid biomarkers as "probable" and "known" in terms of the level of confidence that they attain through the validation process. Probable valid biomarkers may not yet be widely accepted or validated externally but appear to have predictive value for clinical outcomes, whereas known valid status is achieved by those that have been accepted in the breadth of the scientific community.

It is important to realize that the different classes of biomarkers reflect their levels of confidence (Figure 1). This can be thought of in a hierarchical manner, with exploratory biomarkers being potential precursors of clinically useful (probable or known) valid biomarkers [13].

Integrating biomarkers into clinical trials for eventual clinical use by identifying the best or most valid biomarker candidates is not a clearcut process. The term validity, particularly in the field of biomarkers research, is a broad concept that has been used to describe everything from the analytical methods to the characteristics of the biomarkers identified [14] . Validity is also used across multiple industries, not only medical or health disciplines. Therefore,

Figure 1 Biomarker validation. Biomarker development and validation are driven by intended use or fit-for-purpose (FFP). The principle of FFP validation is that biomark-ers with false-positive or false-negative indications pertaining to high patient consequences and risks necessitate many phases of validation. There are five phases of validation that can be executed with the stratified use of various bioinformatical and bibliographical tools as well as different designs, statistical approaches, and modeling: (1) internal validation, (2) external validation, (3) clinical trials (phases I and II; checking for safety and efficacy), (4) large clinical trials (phase III), and (5) continued surveillance. Sensitivity and specificity correlate with the intended purpose of the biomarker, and the level of confidence that a biomarker achieves depends on the phase of validation that has been reached. In ideal cases biomarkers reach surrogate endpoint status and can be used to substitute for a clinical endpoint. This designation requires agreement with regulatory authorities, as the consequences of an ambiguous surrogate endpoint are high.

Figure 1 Biomarker validation. Biomarker development and validation are driven by intended use or fit-for-purpose (FFP). The principle of FFP validation is that biomark-ers with false-positive or false-negative indications pertaining to high patient consequences and risks necessitate many phases of validation. There are five phases of validation that can be executed with the stratified use of various bioinformatical and bibliographical tools as well as different designs, statistical approaches, and modeling: (1) internal validation, (2) external validation, (3) clinical trials (phases I and II; checking for safety and efficacy), (4) large clinical trials (phase III), and (5) continued surveillance. Sensitivity and specificity correlate with the intended purpose of the biomarker, and the level of confidence that a biomarker achieves depends on the phase of validation that has been reached. In ideal cases biomarkers reach surrogate endpoint status and can be used to substitute for a clinical endpoint. This designation requires agreement with regulatory authorities, as the consequences of an ambiguous surrogate endpoint are high.

when referring to biomarkers, validation is sometimes termed qualification for clarity. Biomarker qualification has been defined as a graded fit-for-purpose evidentiary process linking a biomarker with biology and clinical endpoints [15,16].

Traditionally, the validity of clinical biomarkers has become established in a typically lengthy process through consensus and test of time [17]. Now more than ever, clear guidelines for validation are needed, as technological advances have drastically increased biomarker discovery rates. With the recent explosion of "omics" technologies and advancements in the fields of genomics, proteomics, and metabolomics, high-throughput biomarker discovery strategies are now widely used. This has created some unforeseen issues. Biomarker

Biomarker accepted or rejected for suggested use t

Qualification study results reviewed e

Qualification study strategy assessed t

Biomarker context assessed and available data submitted in voluntary data submission t

Biomarker qualification review team recruited (clinical and nonclinical)

Submit request to qualify biomarker for specific use

Figure 2 FDA biomarker qualification pilot process. (Adapted from ref. 17.)

candidate discovery now commonly outruns the rate at which the candidates are being validated, creating a bottleneck in biomarker (assay) development [18,19] . Great efforts are now being undertaken to accelerate the acceptance of biomarkers from exploratory to valid, as the goal of many research teams and drug companies is to streamline the translation of biomarker from basic science and discovery to clinical use [12].

Despite the definitions provided by the FDA and the availability of FDA's Guidance for Industry: Bioanalytical Method Validation in 2001, there is still a lack of sufficient regulatory guidance for biomarker validation. The FDA has designed a qualification process map that sets the foundational framework toward establishing validation guidelines (Figure 2). This pilot structure, to start qualification processes for biomarkers in drug development, is designed around various FDA centers whereby the context and qualification of new biomarkers is assessed. Ultimately they are rejected or accepted for suggested use relative to current biomarkers. This may not be ideal, as it may be problematic to establish new biomarkers accurately based on the current biomark-ers, which are themselves often imperfect relative to a specific endpoint [17]. Nonetheless, this pilot framework will eventually enable more detailed bio-marker translation models, which address some of the remaining issues with the current guidelines, to be developed.

There remains a lack of specific guidelines on which validation process(es) are recommended or expected in order to transition effectively from exploratory to valid biomarkers, or from probable valid biomarkers into known valid biomarkers [13,20] - Confusion still exists with regard to analyses or experiments that need to be performed and data that are both appropriate and sufficient for biomarker (assay) validation [20].

The confusion and inconsistency in the validation process are contributed to partially by the diverse nature of biomarker research [3,20] - Considering the large variety of novel biomarkers, their applications, and associated analytical methods, it is unlikely that FDA regulations or other available guidelines will easily be able to address validation issues associated with all possible research objectives [16,20]. Thus, it is incredibly difficult to establish, let alone use, a specific detailed universal validation guideline [20].

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