Using translational pharmacology biomarkers to drive earlier decision making

19 April 2011  •  Author(s): Magnus Ivarsson, Head of Physiological Biomarkers, Pfizer and Mark Fidock, Head of Quantitative Biomarkers, Research Enabling Group, Pfizer

The current high rate of attrition during drug development is unsustainable. An increasing amount of the cost of developing a new drug is made up of the investment in molecules that fail at some point during the process and the later that failure occurs, the more costly it will be. Recent surveys suggest that the attrition rate in the pharmaceutical industry is now more than 90 per cent from the first in human study to launch1-4. Reducing attrition is now one of the key challenges for the pharmaceutical industry, but before exploring potential ways forward, it is necessary to understand what drives the attrition and causes drug candidates to fail during the development process.

Most candidates fail for some basic reasons e.g. a) the original hypothesis and target is wrong; b) the target mechanism does not translate to human due to a different molecular target distribution or the pharmacology between species is not comparable; c) the molecule fails to reach the desired target in sufficient amounts to be efficacious; d) the molecule cannot be formulated in an acceptable way; e) unexpected clinical safety issues; f) changes in the commercial value of target hypothesis. However, the contribution of these different reasons for the attrition of drug development candidates will naturally change over time as risks are identified and addressed. This is exemplified with the introduction of the improved preclinical screening of drug metabolism and the significant reduction in pharmacokinetic reasons for drug candidate failure that this screening has entailed5.

Across the industry, a number of strategies are being implemented to improve the development success of drug candidates. The strategies can be divided into ‘improved target validation’, ‘improved drug candidates’ and ‘increased early attrition rate’2.

The main focus of this review will be how translational pharmacology biomarkers can be used in the strategy to increase the early attrition rate and thus improve the success rate at later stages. The Biomarkers Definitions Working Group6 defined a biological marker as something which is “a characteristic that is measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.” The generic definition of a biomarker has had the effect that the term biomarker has been widely used and it is therefore imperative that the definition of a biomarker is clearly defined. The generic definition encompasses both disease-related (a biological effect of a drug that is predictive of efficacy in the target disease either in patients or in a human model of the disease) and nondisease related, which is linked to target engagement (a biological effect that indicates that the drug is having the expected pharmacology for its target receptor/enzyme etc). The discussions in this review will focus on the latter type of biomarkers, which has also been called efficacy, target or pharmacology biomarkers.

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