Journal Article

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

Wang, Jibo, Leach, Andrew R., Pairaudeau, Garry, Leeson, Paul D., Weir, Alex, Waring, Michael J., Pennie, William D., Pickett, Stephen D., Mandrell, Sam, Arrowsmith, John, Owen, Robert M., Wallace, Owen

2015

Overview

Key Points This Analysis article describes 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. Safety and toxicology are the largest sources of failure within the data set. The link between calculated physicochemical properties and frequent causes of attrition (preclinical toxicology, clinical safety and human pharmacokinetics) is assessed. Analysis of this data set shows that none of the physicochemical descriptors we examined correlates with preclinical toxicology outcomes. This work is the first to indicate a link between lipophilicity and clinical failure owing to safety issues. The utility of this finding in a prospective sense is discussed. Although control of physicochemical properties is clearly important, this analysis suggests that further stringency in this respect is unlikely to have a significant effect on attrition in development and that additional work is required to address safety-related failures. Attempts to reduce the number of efficacy- and safety-related failures that may be linked to the physicochemical properties of small-molecule drug candidates have been inconclusive owing to the limited size of data sets from individual companies. Waring and colleagues analyse the largest data set compiled so far on the causes of attrition for oral, small-molecule drug candidates, derived from a pioneering data-sharing effort by AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154 / 631/92/613 / 639/638/309/2144 / analysis / Animals / Biomedicine / Biotechnology / Cancer Research / Drug Delivery Systems - methods / Drug Delivery Systems - statistics & numerical data / Drug Delivery Systems - trends / Drug discovery / Drug Discovery - methods / Drug Discovery - statistics & numerical data / Drug Discovery - trends / Drug Evaluation, Preclinical - methods / Drug Evaluation, Preclinical - statistics & numerical data / Drug Evaluation, Preclinical - trends / Drug Industry - methods / Drug Industry - statistics & numerical data / Drug Industry - trends / Drugs, Investigational - administration & dosage / Humans / Medicinal Chemistry / Methods / Molecular Medicine / Pharmaceutical industry / Pharmacology/Toxicology / Product development / Quality management / Statistics / Statistics as Topic - methods / Statistics as Topic - trends