Next‐Generation DILI Biomarkers: Prioritization of Biomarkers for Qualification and Best Practices for Biospecimen Collection in Drug Development

Abstract

The diagnosis and management of drug-induced liver injury (DILI) remains a challenge in clinical trials in drug development. The qualification of emerging biomarkers capable of predicting DILI soon after the initiation of treatment, differentiating DILI from underlying liver disease, identifying the causal entity, and assigning appropriate treatment options after DILI is diagnosed are needed. Qualification efforts have been hindered by lack of properly stored and consented biospecimens that are linked to clinical data relevant to a specific context of use. Recommendations are made for biospecimen collection procedures, with the focus on clinical trials, and for specific emerging biomarkers to focus qualification efforts. FOREWORDThe IQ Drug Induced Liver Injury (IQ DILI) Initiative was launched in June 2016 within the International Consortium for Innovation and Quality in Pharmaceutical Development (also known as the IQ Consortium) to reach consensus and propose best practices on topics related to clinical drug-induced liver injury (DILI) (www.iqdili.org). The IQ Consortium is a leading science-focused, not-for-profit organization addressing scientific and technical aspects of drug development and is composed of 39 pharmaceutical and biotechnology companies. The IQ DILI Initiative is an affiliate of the IQ Consortium, composed of 17 IQ member companies, focused on establishing best practices for monitoring, diagnosing, managing, and preventing DILI. This publication is focused on the prioritization of DILI biomarkers related to hepatocellular injury in clinical trial development for qualification and best practices for biospecimen collection based on an extensive literature review and the consensus achieved in carefully structured discussions between IQ DILI members and academic and regulatory experts.

Biosafety and biobanking: Current understanding and knowledge gaps

“…Several manuscripts contained more specific examples, where the safety of the collected specimens or the operator has improved through novel protocols [9] , [16] , [34] . Such technological innovation positively impacts biospecimens' handling and, consequently, on preserving biological indicators [17] or particular cell types [21] , [22] , [26] , [27] . The concept of safety of biological samples extends beyond the immediate collection and handling of biological material and onto the long-term storage conditions.…”

Pharmacodynamics of tegoprazan and revaprazan after single and multiple oral doses in healthy subjects

“…First, the power of this result is limited due to the small number of subjects, eight subjects per group. Furthermore, although the Food and Drug Administration of the United States has indicated that miR‐122 could be studied further as a biomarker of drug‐induced liver injury, it still requires further and thorough validation 34 . Actually, from the safety data of a clinical development report, it is reported that up to 18.8% of subjects presented liver enzyme elevation after administration of revaprazan 35 and that of tegoprazan was less than 1% 13 …”

Drug-Induced Liver Injury: Highlights and Controversies in the Recent Literature

“…The authors also describe a case of a patient with rhabdomyolysis who developed elevations in AST, ALT, and creatine kinase, while GLDH remained normal until the patient developed hypoxia-induced liver injury [45]. Roth et al reviewed the literature on emerging serum biomarkers of DILI specifically, including GLDH [46]. They highlight the potential advantages of GLDH as a biomarker including no differences in levels based on age or gender, and little intra-subject and inter-subject individual variability in several studies.…”