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

Abstract

One promise of new translational safety biomarkers (TSBs) is their ability to demonstrate that toxicities in animal studies are monitorable at an early stage, such that human relevance of potential adverse effects of drugs can be safely and definitively evaluated in clinical trials. Another is that they would provide an earlier, more definitive and deeper insight to patient prognosis compared with conventional biomarkers. Recent experience with regulatory authorities indicates that resource demands for new TSB qualifications under the current framework are daunting and the rate of their expansion will be slow, particularly in light of mounting financial pressures on the pharmaceutical industry. Sponsors face a dilemma over engaging in safety biomarker qualification consortia. While it is clear new TSBs could be considered catalysts to drug development and that patient health, business and scientific benefits, described here using examples, should outweigh qualification costs, concerns exist that early ambiguities in biomarker interpretations at the introduction of such new TSBs might hinder drug development.

Potential use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th Acute Dialysis Quality Initiative consensus conference

“…Identification of a damage biomarker positive, creatinine negative state may reflect a phase of renal injury and could serve as a specific parameter for drug development to ascertain nephrotoxic potential. Several on-going studies with collaborations from the Predictive Safety Testing consortium with the FDA and EMEA will likely inform this process 29 - 31 . We anticipate that validation of a damage biomarker positive state will be required linking these changes to pertinent clinical outcomes independent of changes in serum creatinine 13 .…”

Scaling and systems biology for integrating multiple organs-on-a-chip

“…122,123 The aforementioned ~4.5 mL and ~4.5 μL blood volumes for a mHu and μHu will place severe constraints on not only the fraction of an organ bioreactor that must be occupied by cells, but also limits the size of in-system sensors and the volume that can be withdrawn for analysis of the system’s state and subsequent control adjustments. The scaling arguments applied to the organs also apply to the instruments that will analyze their performance.…”

Translational biomarkers of acetaminophen-induced acute liver injury

“…The goal for new predictive translational safety biomarkers is to be able to monitor early indications of organ toxicity in clinical trials, so better informed clinical and regulatory decisions can be made and treatment can be stopped or altered before organ injury occurs (Aronson 2005 ; Matheis et al 2011 ; Sistare and DeGeorge 2011 ). The ideal characteristics of translational safety biomarkers of organ injury are that they provide more sensitive and specific information than current clinical chemistry biomarkers, can be detected through robust analytical assays in relevant translational species (rat, dog, mouse or monkey) and in humans, can be measured noninvasively or in accessible fluids like blood or urine, can predict or monitor severity of histopathology in nonclinical species, are specific for organ injury or mechanisms of toxicity that lead to organ injury, are specific to tissue location and are insensitive to nontoxic perturbations (exercise, diet, age, and other diseases and toxicities to other organs) (Amacher 2010 ; Muller and Dieterle 2009 ; Sasseville et al 2014 ; Sistare and DeGeorge 2011 ; Mattes personal communication). The translational aspect, i.e., the ability of the biomarker to have similar responses in different species, enables comparisons of nonclinical studies with clinical studies.…”