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A systematic approach to preclinical and clinical safety biomarker qualification incorporating Bradford Hill’s principles of causality association

Chetty, Rajkumar, Ozer, Josef, Lanevschi, Anne, Schuppe-Koistinen, Ina, McHale, Duncan, Pears, John, Vonderscher, Jacky, Sistare, Frank and Dieterle, Frank (2010) A systematic approach to preclinical and clinical safety biomarker qualification incorporating Bradford Hill’s principles of causality association. Clinical Pharmacology & Therapeutics, 88 (2). pp. 260-262. ISSN 0009-9236


A number of pharmaceutical companies have become involved in exploring novel safety biomarkers based on the premise that improved predictors or earlier reporters of toxicity events will reduce the rate of drug attrition and repurpose resources to other improvements in R&D. Until recently, advances in safety biomarker research have lagged behind advances in efficacy-based biomarkers used in drug discovery and development. There are currently a number of pharmaceutical-academic-regulatory collaborations e.g. the C-Path Institute’s Predictive Safety Testing Consortium (PSTC), the Health and Environmental Sciences Institute (HESI-US), The International Life Sciences Institute (ILSI-worldwide) and Innovative Medicine Inititative’s Safer And Faster Evidence-based Translation consortium (IMI SAFE-T) aim to foster collective knowledge in the qualification of novel safety biomarkers to reduce new chemical entity attrition rates. While this is a laudable goal, scientific processes and appropriate standards for ‘prioritising’, ‘validating’ and ‘qualifying’ or candidate biomarkers are not clearly established and recognised.
The recent FDA/EMEA guidelines on qualification of biomarkers are an important step in the regulatory processes of biomarker qualification1. Still, there are a number of unanswered concerns regarding what constitutes a useful biomarker with added value to historical biomarkers and what are the optimal ways of collecting and evaluating scientific evidence for the clinical qualification of a biomarker. The focus of this publication is to provide clarity on what is meant by the prioritisation and qualification of biomarker candidates. It is proposed that the well-known concept of Bradford Hill’s causality association criteria could be applied as a general framework for this purpose. Sir Austin Bradford Hill established the following nine criteria for causation (does factor A cause disorder B) to separate the causal and non-causal mechanisms of the observed associations. Although developed for use in the field of occupational medicine, these criteria (strength of association, consistency, temporality, biological gradient, plausibility, coherence, specificity, experimental evidence and analogy) can be used in many situations to establish causal relationships and we are proposing that Hill’s criteria offer a useful approach to aid the qualification of safety biomarkers.

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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16


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