An analysis of the attrition of drug candidates from four major pharmaceutical companies

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The pharmaceutical industry remains under huge pressure to address the high attrition rates in drug development. Attempts to reduce the number of efficacy- and safety-related failures by analysing possible links to the physicochemical properties of small-molecule drug candidates have been inconclusive because of the limited size of data sets from individual companies. Here, we describe the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physicochemical properties of compounds and clinical failure due to safety issues. The results also suggest that further control of physicochemical properties is unlikely to have a significant effect on attrition rates and that additional work is required to address safety-related failures. Further cross-company collaborations will be crucial to future progress in this area.

Reducing the high attrition rates in drug development continues to be a key challenge for the pharmaceutical industry. The number of failures of small-molecule drug candidates due to poor pharmacokinetic profiles seems to have diminished significantly in recent years, but this has been accompanied by a shift towards failures due to efficacy and safety issues, and overall attrition rates remain high. However, ascribing single reasons for compound failure could be an oversimplification because there may be multiple factors contributing to the decision to terminate the development of a compound.

Over the past two decades, multiple studies have proposed benefits (in terms of reduced likelihood of attrition) from controlling the physicochemical properties of compounds, such as size, lipophilicity and polarity, based on analyses of data sets of approved oral small-molecule drugs and investigational compounds. Beginning with Lipinski's toxicology study, initial studies focused on a link between physicochemical properties and the likelihood of attrition owing to poor absorption, distribution, metabolism and excretion (ADME) characteristics. More recently, attention has focused on the influence of physicochemical properties on promiscuity and in vivotoxicological outcomes. It should, however, be noted that the manner in which analyses such as those in Refs (and similar analyses) have been carried out has recently been criticized; in particular, critics have highlighted that the use of averaged or categorized (binned) data can exaggerate the strength of correlations

Clearly, the benefits of establishing a link between important end points such as an in vivo toxicology outcome and simple descriptors such as logP and PSA (which can be easily calculated before synthesis) are highly attractive. However, there are several problems encountered in attempting to do so. First, the outcome of toxicology studies can be both subjective and context-dependent. In considering whether a toxicology finding is sufficient to halt progression of a compound to human subjects, several factors must be considered, including the following: the severity and reversibility of the finding; the margin between the concentration of the compound at which toxicity is observed compared with the concentration needed to show beneficial effects (also known as the therapeutic index); the risk–benefit ratio in the intended disease setting; the likelihood of such an effect translating to humans; and the ability to monitor and treat any subsequent consequences. As such, the decision to stop a drug candidate for toxicological reasons is a complex and nuanced judgement..