Review, News & Views, Perspectives, Hypotheses and Analyses

Co-developing a drug with a diagnostic to create a stratified medicine — a therapy that is targeted to a specific patient population on the basis of a clinical biomarker — presents challenges for product developers, regulators, payers and physicians. With the aim of developing a shared framework and tools for addressing these challenges, this article presents an analysis using data from case studies in oncology and Alzheimer's disease, coupled with integrated computational modelling of clinical outcomes and economic value, to quantify the effects of decisions on key issues such as the design of clinical trials.

In the past 15 years, it has become clear that physicochemical properties of drug candidates, such as lipophilicity and molecular mass, have an important influence on the likelihood of compound-related attrition during development. By analysing the properties of compounds described in patents from leading pharmaceutical companies between 2000 and 2010, this article indicates that a substantial part of the industry has not modified its drug design practices accordingly and is still producing compounds with suboptimal physicochemical profiles.

Schiöth and colleagues examine the drugs approved by the US Food and Drug Administration over the past 30 years and analyse the interactions of these drugs with therapeutic targets encoded by the human genome, identifying 435 effect-mediating drug targets. They also analyse trends in the introduction of drugs that modulate previously unexploited targets, and discuss the network pharmacology of the drugs in the data set.

To investigate whether some strategies have been more successful than others in the discovery of new drugs, this article analyses the discovery strategies and the molecular mechanism of action for 259 new drugs that were approved by the US Food and Drug Administration between 1999 and 2008. Observations from this analysis — such as the fact that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches in an era in which the major focus was on target-based approaches — could have important implications for efforts to increase the productivity of drug research and development.

Although investment in pharmaceutical research and development (R&D) has increased substantially in recent decades, the lack of a corresponding increase in the output in terms of new drugs being approved indicates that therapeutic innovation has become more challenging. Here, using a large database that contains information on R&D projects for more than 28,000 compounds investigated since 1990, Riccaboni and colleagues examine the factors underlying the decline in R&D productivity, which include an increasing concentration of R&D investments in areas in which the risk of failure is high.

A common assumption in current drug discovery strategies is that compounds with highin vitro potency at their target(s) have a greater potential to translate into successful, low-dose therapeutics, which is reflected in screening cascades with in vitro potency embedded as an early filter. This analysis of the publicly available ChEMBL database, which includes more than 500,000 drug discovery and marketed oral drug compounds, suggests that the perceived benefit of high in vitropotency may be negated by poorer absorption, distribution, metabolism, elimination and toxicity (ADMET) properties.

Understanding the factors that promote drug innovation is important both for improvements in health care and the future of organizations engaged in the field. To investigate these factors, Kneller identifies the inventors of 252 new drugs approved by the US Food and Drug Administration from 1998 to 2007 and their places of work, and classifies these drugs according to innovativeness. This article presents a comprehensive analysis of these data, which highlight the strong contribution of biotechnology companies, particularly in the United States, to innovative drug discovery, and discusses potential contributing factors to the trends observed.

Improving R&D productivity is crucial to ensuring the future viability of the pharmaceutical industry and advances in health care. This article presents a detailed analysis, based on comprehensive, recent, industry-wide data, to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity, and proposes strategies that could have the most substantial impact in enhancing R&D productivity.

This article investigates pharmaceutical innovation by analysing data on the companies that introduced the ∼1,200 new drugs that have been approved by the US FDA since 1950. Implications of this analysis — which shows that the rate of new drug output in this period has essentially been constant despite the huge increases in R&D investment — are discussed, as well as options to achieve sustainability for the pharmaceutical industry.

Here, the authors use bibliometrics and related data-mining methods to analyse PubMed abstracts, literature citation data and patent filings. The analyses are used to identify trends in disease-related scientific activity that are likely to give new therapeutic opportunities.

The recent determination of several crystal structures of G protein-coupled receptors (GPCRs) is providing new opportunities for structure-based drug design. This article analyses the state of the art in the prediction of GPCR structure and the docking of potential ligands on the basis of a community-wide, blind prediction assessment — GPCR Dock 2008 — that was carried out in coordination with the publication of the human adenosine A_2Areceptor structure in 2008 and public release of the three-dimensional coordinates.

By analysing the physicochemical properties of a database of hits and leads, Keserü and Makara conclude that high-throughput screening, as well as hit-to-lead optimization practices in general, are responsible for the unfavourable physicochemical profile of recent leads and clinical candidates. Major adjustments may be needed to enable a balanced lead-evolution process and reduce the likelihood of high compound-related attrition in clinical trials.

Understanding the molecular mechanisms underlying the effects of efficacious drug combinations could aid the discovery of novel combinations and multi-targeted drugs. This article presents an extensive investigation of drug combinations for which rigorous analytical information is available in published literature, which illustrates several general types of combination mechanisms and highlights the potential value of molecular interaction profiles for studying such mechanisms.

Despite the wide acceptance of drug-like principles such as the 'rule of five', this analysis of molecules currently being synthesized in leading pharmaceutical companies reveals that their physical properties differ significantly from those of recently discovered oral drugs. The marked increase in lipophilicity in particular could increase the likelihood of attrition in drug development.