A Systematic Approach to Preclinical and Clinical Safety Biomarker Qualification Incorporating Bradford Hill's Principles of Causality Association

Abstract

The recently issued FDA/EMEA (US Food and Drug Administration/European Medicines Agency) guidelines pertaining to qualification of biomarkers are an important development in the regulatory approval process for new drug applications. 1,2 A qualified biomarker approved by regulatory authorities allows sponsors across industry to use that marker in new drug applications on the basis of a single submission rather than requiring each sponsor to present a separate justification with each new drug application. Nevertheless, there are a number of unanswered questions regarding the specific criteria that such a biomarker should meet in order to be considered as adding value to historical clinical end points and preclinical pathology observations. There are also questions regarding the optimal methods of collecting and evaluating scientific evidence for the clinical qualification of a biomarker. We propose a novel application to assist and accelerate the drug development process by prioritizing biomarker candidates and evidence, an application based on Bradford Hill's principles of causality association. The Process of regulaTory Biomarker QualificaTionFollowing the FDA/EMEA review of requirements related to preclinical safety biomarkers of nephrotoxicity, there is now clarity about the evidentiary data that regulators expect to be shown in support of applications for the qualification of biomarkers for use in drug development. Furthermore, sev eral criteria that have been applied to preclinical biomarker qualification may be applicable to the clinical setting as well, with the exception of the requirement for access to biopsy samples of target organs for histopathological assessment. The final FDA/EMEA qualification of preclinical nephro toxicity biomarkers identified limitations of the data sets, including a lack of additional recovery studies, an extensive use of retrospective data, basing histopathology scores on use of a single kidney section, use of the current good lab oratory practice pathology review standard for biomarker qualification, and the applicability of bio marker immuno histochemical data to indicate the anatomical location of injury within the kidney. 1,3,4 This feedback from regulatory authorities is a guide for biomarker researchers in the phar maceutical industry and academia to organize their approach to the crucial task of attaining qualification of safety and additional biomarkers.The starting point for qualification is to clearly identify and characterize the requirements a biomarker is expected to fulfill for the sponsor and its context for use in a new drug appli cation. This requires a clear definition of the problem to be addressed by use of the candidate biomarker and the stage of drug development at which it will be applied. There is limited literature describing the criteria for qualification of clinical biomarkers for drug testing. Altar et al. 5 described a set of seven evidentiary standards for biomarkers and diagnostics in a systematic manner. The biomarkers were graded from A (substan...

Categorization of Abuse Potential–Related Adverse Events

“…7 The principles and processes of establishing adverse-reaction causality have been clear for decades but are rarely applied in clinical trials. 8,9 Possibly, one reason for this is that in clinical trials patients are carefully selected to exclude many potential event confounders, and concurrent medications are usually excluded or kept at constant doses. Trials attempt to make the test agent the major variable.…”

“…Causality for treatment‐emergent adverse events can only be assessed properly in the context of individual cases and by using structured algorithms and trained observers and raters . The principles and processes of establishing adverse‐reaction causality have been clear for decades but are rarely applied in clinical trials . Possibly, one reason for this is that in clinical trials patients are carefully selected to exclude many potential event confounders, and concurrent medications are usually excluded or kept at constant doses.…”

Promise of New Translational Safety Biomarkers in Drug Development and Challenges to Regulatory Qualification

“…This 'broad-use' clinical qualification claim was not accepted by regulatory authorities despite, for example, the summary of hundreds of published references supporting the strong performance of urinary microalbumin as a clinical biomarker of renal injury and dysfunction. None of the five biomarkers was thought to have been sufficiently qualified for general use in early clinical studies (Phase I study) for detecting drug-induced acute kidney injury, and, in such cases, it was deemed that the utility of these biomarkers should be judged on a case-by-case basis [37,105]. Regulatory authorities indicated that a number of further clinical studies for extensive evaluation would be needed before widespread use of the biomarkers for detection of drug-induced kidney injury in humans.…”

Biomarkers for knee osteoarthritis: new technologies, new paradigms

“…Early studies address repeatability in single centers, or in a few centers using identical equipment. At the same time, biological and clinical validity may be approached tentatively using the Bradford Hill [9][10][11] criteria, for example with small cross-sectional or interventional studies. Only later, after extensive efforts to establish that the biomarker measures are the same in different centers, using different equipment in different jurisdictions, can definitive outcome studies be performed.…”