Drug attrition

The reasons for drug attrition have evolved over the years over the last decade, lack of safety (both non-clinical and clinical) remains the major cause of attrition during clinical development, which accounts for approximately 35 to 40% of all drug discontinuation (see Table 13.1).la lc More worrying is the fact that there is no clear trend toward a reduction of the attrition owing to safety reasons. 

De-risking developmental toxicity-mediated drug attrition in the pharmaceutical industry... 

Car BD. Enabling technologies in reducing drug attrition due to safety failures. American Drug Discov 2006 1 53-56. 

Car BD. Enabling Technologies in Reducing Drug Attrition Due to Safety Failures. Am Drug Discov 2006 1 53-6. 

Cells and subcellular fractions from humans and many preclinical species are readily available. These reagents make it possible to make interspecies extrapolations easily. At one time, a major reason cited for early drug attrition was pharmacokinetic failure, attributable to the difficulty in extrapolating pharmacokinetic behavior from animals to humans. In this author s experience, unexpected pharmacokinetic performance in humans is now a rare event. In addition, it is now commonplace to obtain very mechanistic information revealing the probability of observing quite specific molecular events (e.g., toxicity) in humans (Mutlib et ah, 2000). 

CV safety issues are a major cause of drug attrition in both the nonclinical and clinical phases of drug discovery and development, and an estimated 45% of drug withdrawals during the postmarketing phase are atttibuted to adverse CV events, such as myocardial infarction, arrhythmia, and cardiac arrest (Laverty et al., 2011 Pierson et al., 2013). 

Bowes J, Brown AJ, Hamon J, Jarolimek W, Sridhar A, Waldron G, Whitebread S (2012). Reducing safety-related drug attrition the use of in vitro pharmacological profiling. Nat Rev Drug Discov 11 909-922. 

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