John-Michael Sauer

Qualification of a biomarker for use in a medical product development program requires a statistical strategy that aligns available evidence with the proposed context of use (COU), identifies any d...

Safety biomarkers are important drug development tools, both preclinically and clinically. It is a straightforward process to correlate the performance of nonclinical safety biomarkers with histopathology, and ideally, the biomarker is useful in all species commonly used in safety assessment. In clinical validation studies, where histopathology is not feasible, safety biomarkers are compared to the response of standard biomarkers and/or to clinical adjudication. Worldwide, regulatory agencies have put in place processes to qualify biomarkers to provide confidence in the manner of use and interpretation of biomarker data in drug development studies. This paper describes currently qualified safety biomarkers which can be utilized to monitor for nephrotoxicity and cardiotoxicity and ongoing projects to qualify safety biomarkers for liver, skeletal muscle, and vascular injury. In many cases, the development and use of these critical drug development tools is dependent upon partnerships and the precompetitive sharing of data to support qualification efforts.

Background: Currently, 2 coprimary end points are used by health authorities to determine the effectiveness of therapeutic interventions in patients with Crohn’s disease (CD): symptomatic remission (patient-reported outcome assessment) and endoscopic remission (ileocolonoscopy). However, there is lack of accepted biomarkers to facilitate regulatory decision-making in the development of novel therapeutics for the treatment of CD. Methods: With support from the Helmsley Charitable Trust, Critical Path Institute formed the Crohn’s Disease Biomarkers preconsortium (CDBpC) with members from the pharmaceutical industry, academia, and nonprofit organizations to evaluate the CD biomarker landscape. Biomarkers were evaluated based on biological relevance, availability of biomarker assays, and clinical validation data. Results: The CDBpC identified the most critical need as pharmacodynamic/response biomarkers to monitor disease activity in response to therapeutic intervention. Fecal calprotectin (FC) and serum C-reactive protein (CRP) were identified as biomarkers ready for the regulatory qualification process. A number of exploratory biomarkers and potential panels of these biomarkers was also identified for additional development. Given the different factors involved in CD and disease progression, a combination of biomarkers, including inflammatory, tissue injury, genetic, and microbiome-associated biomarkers, will likely have the most utility. Conclusions: The primary focus of the Inflammatory Bowel Disease Regulatory Science Consortium will be development of exploratory biomarkers and the qualification of FC and CRP for IBD. The Inflammatory Bowel Disease Regulatory Science Consortium, focused on tools to support IBD drug development, will operate in the precompetitive space to share data, biological samples for biomarker testing, and assay information for novel biomarkers.

Current blood biomarkers are suboptimal in detecting drug‐induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of 14 promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n = 192 and n = 81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n = 55 and n = 92) and DILI patients (n = 98, n = 28, and n = 143) were assayed for microRNA‐122 (miR‐122), glutamate dehydrogenase (GLDH), total cytokeratin 18 (K18), caspase cleaved K18, glutathione S‐transferase α, alpha‐fetoprotein, arginase‐1, osteopontin (OPN), sorbitol dehydrogenase, fatty acid binding protein, cadherin‐5, macrophage colony‐stimulating factor receptor (MCSFR), paraoxonase 1 (normalized to prothrombin protein), and leukocyte cell‐derived chemotaxin‐2. Most candidate biomarkers were significantly altered in DILI cases compared with healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase than miR‐122, and there was a surprisingly wide inter‐ and intra‐individual variability of miR‐122 levels among healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver‐related death or transplantation within 6 months of DILI onset. Prediction of prognosis among DILI patients using the Model for End‐Stage Liver Disease was improved by incorporation of K18 and MCSFR levels. Conclusion: GLDH appears to be more useful than miR‐122 in identifying DILI patients, and K18, OPN, and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management.

Biomarkers are ubiquitously used within drug development programs in both nonclinical species and in humans to assess safety and efficacy of novel compounds. To routinely apply such novel biomarkers with certainty, a well-defined data package is necessary for review and endorsement by regulatory agencies including the US Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceuticals and Medical Devices Agency. This type of endorsement is known as regulatory qualification. Novel approaches are being applied to speed the process, lower the resource intensity, and increase the accessibility of biomarker qualification data and it is likely that consortia will continue to play a fundamental role in the qualification process by bringing together like-minded stakeholders focused on specific tools to accelerate drug development. This article will focus on learnings from the previous three nonclinical biomarker qualification projects, as well as discuss the progression of preclinical biomarker projects into the clinical qualification space and the current strategy for the use of nonclinical biomarker data in the translational qualification of clinical biomarkers; much like nonclinical information is used in the approval of drug development candidates. Impact statement: This minireview provides an overview of the history of preclinical biomarker qualification by summarizing the three examples of this type of qualification with US Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceuticals and Medical Devices Agency. In addition, an overview of the biomarker qualification process is included to educate key stakeholders with links to relevant white papers that provide information on current evidentiary considerations. The manuscript also provides new information on the evolution of the role that preclinical qualification plays in clinical qualification of biomarkers and the novel approaches that are being utilized to improve the process.

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