Opinion in 2010

Data on the fraction of protein-bound drug are frequently used to guide chemical structure design and to prioritize compounds forin vivostudies. Here, the authors highlight how these practices are misleading and could result in the wrong compounds being progressed through discovery programmes.

Regulatory and economic incentives to develop drugs for rare diseases, known as orphan drugs, have resulted in substantial improvements in the treatment for patients with some such diseases. However, the advent of orphan drug development has also raised several questions, from the definition of rarity, to the pricing of orphan drugs and their impact on health-care systems. Tambuyzer considers such questions and related misconceptions with the aim of aiding future progress in the field.

Developing optimal combination strategies for molecularly targeted anticancer drugs is substantially more complex than for traditional chemotherapies. Here, Doroshow and colleagues discuss the lessons learned from the evaluation of combinations of molecularly targeted anticancer agents by the US National Cancer Institute (NCI), and highlight several new approaches that the NCI has initiated to improve the effectiveness of such combinations.

Currently, drug development is based on a consecutive phase model and Phase I clinical trials often have tolerability as their primary objective. Here, Cohen advocates new concepts for drug development that are based on pharmacological knowledge about the effects of the drug and an adaptive, cyclical development process.

The development of new protease inhibitors has proved challenging in recent years. In their Perspective, Drag and Salvesen discuss the underlying reasons for this, and how lessons learned from failures can inform future research directions in the field.

The permeation of a drug across a biological membrane is one of the most important determinants of the pharmacokinetics of a drug. Here, the authors discuss the contribution of passive transport and carrier-mediated transport to the total permeation of a drug, focusing onin vitro and in vivoresults, as well as highlighting the implications for drug discovery.

Efforts to repeat the success of pioneering molecularly targeted cancer drugs, such as trastuzumab, for particular patient populations have been hampered by factors such as a lack of correlation between the molecular markers used to select patients for treatment and the drug response. This article highlights lessons learned from the development of drugs targeting members of the epidermal growth factor receptor family, and discusses strategies to decrease the risk of failure in clinical trials by more effectively integrating molecular diagnostics into anticancer drug discovery and development.

Biomarker strategies are increasingly being applied in drug development to address the challenges posed by heterogeneity in the underlying mechanisms of disease processes and inter-patient variability in drug responses. With the aim of enhancing understanding of the regulatory significance of such biomarker data by regulators and sponsors, the US FDA initiated a programme in 2004 to allow sponsors to submit exploratory data voluntarily, without immediate regulatory impact. This article discusses a selection of case studies from the first 5 years of this programme, highlighting lessons learned.

This article explores some of the challenges and opportunities in developing personalized treatment for patients with cancer, which could improve outcomes, reduce toxicity, improve efficiency in drug development and help control the rising costs of cancer care.

Computational chemistry — in particular, virtual screening — can provide valuable contributions in hit and lead discovery. However, it seems that there are relatively few examples so far of drug discovery projects in which virtual screening has been the key contributor. This article discusses aspects that could be limiting the potential of virtual screening, and proposes key directions in which significant progress could be made.

Advanced therapy medicinal products (ATMPs) offer hope for the treatment of diseases for which therapeutic options are currently lacking. This article discusses the regulatory role of the Committee for Advanced Therapies at the European Medicines Agency, highlighting issues and challenges observed in ATMP development.

Long-term therapeutic options for the treatment of obesity are limited. In his Perspective, Cao discusses the functions of the vasculature within adipose tissue — particularly its role in tissue growth and development, and the potential of targeting adipose tissue angiogenesis as a novel anti-obesity therapy.