Why Qualify Biomarkers

More often than not, new biomarkers are judged on the basis of whether they have been subjected to a process of validation. Strictly speaking, validation is a process to "establish, or illustrate the worthiness or legitimacy of something" [44]. For judgments of biomarker worthiness or legitimacy, an assessment is needed of both (1) the assay or analytical method to measure the biomarker, and (2) the performance against expectations of the biomarker response under a variety of biological or clinical testing conditions. The term validation reasonably applies to the first of these, the process by which the technical characteristics of an assay of a biomarker are defined and determined to be appropriate for the desired measurements [45]. Thus, Wagner has defined validation as the "fit-for-purpose process of assessing the assay and its measurement performance characteristics, determining the range of conditions under which the assay will give reproducible and accurate data" [46] - Even for assay validation, the concept of fit - for- purpose is introduced, which connotes that the process depends on context, and its level of rigor depends on the application of and purpose for the assay. Thus, a biomarker used for an exploratory purpose may not require the more rigorous analytical validation required of a biomarker used for critical decision making. The elements of biomarker assay validation that would be addressed for different categories of biomarker data and for different purposes have been discussed in this book and elsewhere, and they essentially constitute a continuum of bioanalytical method validation [45,47] - Such technical bioanalytical assay method validation is a familiar process and does not generally pose a problem for an organization embarked on assay development [45].

The term validation has also been applied to a process by which a new test method is confirmed to be broadly applicable to interpretation of biological meaning in a wide variety of contexts and uses, such as in the validation of alternatives to animal tests as overseen by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) [48]. This process involving assessment of biological performance expectations is in contrast to that of qualification, which Wagner defines as "the fit-for-purpose evidentiary process of linking a biomarker with biological processes and clinical endpoints" [46]. As for assay validation, this fit-for-purpose biological qualification concept marries the nature and extent of testing rigor to the intended application. In the case of biomarkers applied to predicting human outcomes, four general phases have been proposed [49] , and as the level of qualification progresses, the utility of a biomarker in clinical use increases [46].

In the case of biomarkers of safety (i.e., those that are used to predict or diagnose adverse responses to drug treatment), this qualification process will necessarily involve certain steps. As with qualification of a clinical disease or outcome marker, these steps link biomarker results with biological processes and endpoints. For example, in qualifying a biomarker for nonclinical use, the levels of a protein biomarker in urine may be correlated with certain chemically induced microscopic histopathology lesions in the kidneys of treated animals and thus serve as a noninvasive diagnostic of the appearance of that lesion. As with a clinical disease or outcome marker, qualification of such a marker could proceed in stages. For the example given, an initial stage may be the correlation described, using a variety of treatments that produce only that lesion measured. Such a correlation could establish the sensitivity of the biomarker. However, establishing the specificity of that biomarker for that particular lesion would require a number of treatments that did not produce the lesion being monitored, but instead produce no lesions in the kidney or anywhere else, produced different lesions in the kidney, and/or produced lesions in different organs. Furthermore, the diversity of chemical treatments (i.e., structural and mechanistic diversity) would also need to be considered in the qualification such that a variety of mechanisms underlying the genesis and progression of the lesion can be evaluated.

Clearly, more data could support a higher level of qualification and thus a higher level of utility. For biomarker qualification, the highest phase or level of qualification is the status surrogate endpoint, in which case the biomarker can, in fact, substitute for and serve as the new standard clinical endpoint of how a patient feels, functions, or will survive: for example, in efficacy determinations to support marketing approval decisions. Qualified biomarkers that fall short as surrogate endpoints are nevertheless extremely valuable for both drug development and the general practice of medicine. The key to appreciating the value that will come from opportunities to deploy such biomarkers appropriately is in revealing a thorough understanding of their inherent strengths and limitations. In the early steps of designing studies to test sensitivity and specificity aspects of a biomarker^ performance to reveal that thorough understanding, the strategy may be relatively clear. For safety biomarker qualification, the first and most important attributes to benchmark are knowledge of the biomarker link to biology and outcome, sufficient test sensitivity, and minimizing false test negatives. Evaluating the response of a new proposed biomarker in animals against biomarkers in conventional use using an agreed- upon set of well- recognized toxicants known to induce the desired organ injury is a fairly straightforward strategy. Pivotal, however, to the successful execution of such studies is to provoke a sufficient number of cases where the timing of the samples taken and the choice of dose levels will yield subtle and mild treatment-related effects at the boundary between normal and abnormal. A full spectrum of histologic treatment-related lesions from very slight, to slight, mild, moderate, marked, and severe will be important in this regard for evaluating biomarker sensitivity.

The approaches taken for qualification of a safety biomarker for clinical uses will necessarily be different from those taken for nonclinical uses. Clearly, one cannot expect to have studies with healthy subjects intentionally exposed to a variety of toxicants, nor can one regularly use microscopic histopathology as a benchmark for clinical toxicity. Nonetheless, the goal is to reproducibly link the biomarker to a clinical outcome currently recognized and widely accepted as adverse. For certain types of drug-induced injury, there are stan-dard-of-care treatments that unfortunately are associated with a known incidence of drug - -nduced injury. As an example, aminoglycoside antibiotic treatment is associated with a significant incidence of nephrotoxicity [50], mirroring the effects seen in animal models. Similarly, isoniazid treatment has a known risk of hepatotoxicity -51] - Thus, one approach to safety biomarker qualification in the clinic is to monitor novel biomarker levels longitudinally over the course of such a treatment and compare these with the current gold standard commonly used clinical biomarkers and outcomes [52] - Of course, one can complement these studies with those examining biomarker levels in patients with organ injury of a disease etiology [53].

The number of known agents appropriate for testing the sensitivity of safety biomarkers for certain target organ toxicities may be limited. It is generally expected that the number of studies conducted to evaluate sensitivity should reasonably represent a high percentage of the known but limited diverse mechanisms available for testing in animal and human studies. If the mechanisms are varied for each test agent and sensitivity performance remains high, the biomarker will probably find strong use potential. Specificity tests then become very important considerations in a qualification strategy. The number of test compounds that could be deployed to assess the false-positive test rate is far more expansive than the number of known compounds for testing sensitivity. Specificity testing therefore becomes a highly individualized dimension to a biomarker biological qualification strategy for biomarkers that pass tests of sensitivity. The two critical questions to address are whether (1) there are alternative tissue sources to account for alterations in test safety biomarker levels, and (2) whether there are benign, nontoxicologic mechanisms to account for alterations in test biomarker levels. To evaluate specificity, therefore, a prioritized experimental approach should be taken using logical reasoning to avoid the testing burdens of an endless number of possible studies.

The ultimate goal of these studies is the qualification to the level of what Wagner et al. define as a characterization biomarker [49], a biomarker "associated with adequate preclinical sensitivity and specificity and reproducibly linked clinical outcomes in more than one prospective clinical study in humans." Such a level of qualification then supports the regulatory use of these biomarkers for safety monitoring in early clinical studies with a new pharmaceutical candidate. A strong case has been made that for safety biomarkers for regulatory decision-making purposes, where the rigor of supporting evidence would be expected to be high, that only fully qualified or "characterization" biomarkers are appropriate, and that there is really no regulatory decision-making role for exploratory and "emerging" or "probable valid" biomarkers. In this regard, measurements of such unqualified biomark-ers in animal studies used to support the safe conduct of clinical trials would not be expected to contribute unambiguously and sufficiently to study interpretation, should not require submission to regulatory authorities, and therefore the exploration of their utility in such highly regulated studies should be encouraged [54] in order to accelerate the pace of biomarker evaluations and understanding.

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