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Showing papers in "Nature Reviews Drug Discovery in 2008"


Journal ArticleDOI
TL;DR: The features of nanoparticle therapeutics that distinguish them from previous anticancer therapies are highlighted, and how these features provide the potential for therapeutic effects that are not achievable with other modalities are described.
Abstract: Nanoparticles — particles in the size range 1–100 nm — are emerging as a class of therapeutics for cancer. Early clinical results suggest that nanoparticle therapeutics can show enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumours and active cellular uptake. Here, we highlight the features of nanoparticle therapeutics that distinguish them from previous anticancer therapies, and describe how these features provide the potential for therapeutic effects that are not achievable with other modalities. While large numbers of preclinical studies have been published, the emphasis here is placed on preclinical and clinical studies that are likely to affect clinical investigations and their implications for advancing the treatment of patients with cancer.

3,975 citations


Journal ArticleDOI
TL;DR: The biological rationale for the novel uses of inhibitors or activators of CA activity in multiple diseases is discussed, and progress in the development of specific modulators of the relevant CA isoforms is highlighted, some of which are now being evaluated in clinical trials.
Abstract: Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including gluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth and virulence of various pathogens. In addition to the established role of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently emerged that CAIs could have potential as novel anti-obesity, anticancer and anti-infective drugs. Furthermore, recent studies suggest that CA activation may provide a novel therapy for Alzheimer's disease. This article discusses the biological rationale for the novel uses of inhibitors or activators of CA activity in multiple diseases, and highlights progress in the development of specific modulators of the relevant CA isoforms, some of which are now being evaluated in clinical trials.

2,649 citations


Journal ArticleDOI
TL;DR: This Review discusses the emerging important biological functions of the nitrate–nitrite–NO pathway, and highlights studies that implicate the therapeutic potential of nitrate and nitrite in conditions such as myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration.
Abstract: The inorganic anions nitrate (NO3-) and nitrite (NO2-) were previously thought to be inert end products of endogenous nitric oxide (NO) metabolism However, recent studies show that these supposedly inert anions can be recycled in vivo to form NO, representing an important alternative source of NO to the classical L-arginine-NO-synthase pathway, in particular in hypoxic states This Review discusses the emerging important biological functions of the nitrate-nitrite-NO pathway, and highlights studies that implicate the therapeutic potential of nitrate and nitrite in conditions such as myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration

2,228 citations


Journal ArticleDOI
TL;DR: The accumulation of unfolded proteins in the endoplasmic reticulum represents a cellular stress induced by multiple stimuli and pathological conditions, which triggers an evolutionarily conserved series of signal-transduction events, which constitutes the unfolded protein response.
Abstract: The accumulation of unfolded proteins in the endoplasmic reticulum (ER) represents a cellular stress induced by multiple stimuli and pathological conditions. These include hypoxia, oxidative injury, high-fat diet, hypoglycaemia, protein inclusion bodies and viral infection. ER stress triggers an evolutionarily conserved series of signal-transduction events, which constitutes the unfolded protein response. These signalling events aim to ameliorate the accumulation of unfolded proteins in the ER; however, when these events are severe or protracted they can induce cell death. With the increasing recognition of an association between ER stress and human diseases, and with the improved understanding of the diverse underlying molecular mechanisms, novel targets for drug discovery and new strategies for therapeutic intervention are beginning to emerge.

1,668 citations


Journal ArticleDOI
TL;DR: Some of the key characteristics of protein therapeutics are overviewed, a new classification of these proteins according to their pharmacological action is suggested and this article summarizes the more than 130 protein therapeuticals used currently and suggests a new classifications.
Abstract: Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic--human insulin--25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacological action.

1,654 citations


Journal ArticleDOI
TL;DR: The most common functional groups that are amenable to prodrug design are described, and examples of prodrugs that are either launched or are undergoing human trials are highlighted.
Abstract: Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

1,412 citations


Journal ArticleDOI
TL;DR: The central role of lipid chaperones — the fatty acid-binding proteins (FABPs) — in lipid-mediated biological processes and systemic metabolic homeostasis through the regulation of diverse lipid signals is discussed, and their therapeutic significance is highlighted.
Abstract: Lipids are vital components of many biological processes and crucial in the pathogenesis of numerous common diseases, but the specific mechanisms coupling intracellular lipids to biological targets and signalling pathways are not well understood. This is particularly the case for cells burdened with high lipid storage, trafficking and signalling capacity such as adipocytes and macrophages. Here, we discuss the central role of lipid chaperones — the fatty acid-binding proteins (FABPs) — in lipid-mediated biological processes and systemic metabolic homeostasis through the regulation of diverse lipid signals, and highlight their therapeutic significance. Pharmacological agents that modify FABP function may provide tissue-specific or cell-type-specific control of lipid signalling pathways, inflammatory responses and metabolic regulation, potentially providing a new class of drugs for diseases such as obesity, diabetes and atherosclerosis.

1,320 citations


Journal ArticleDOI
TL;DR: This article aims to provide a comprehensive overview of the five main human GPCR families with a focus on gene repertoire, general ligand preference, common and unique structural features, and the potential for future drug discovery.
Abstract: G protein-coupled receptors (GPCRs) are the largest family of membrane-bound receptors and also the targets of many drugs. Understanding of the functional significance of the wide structural diversity of GPCRs has been aided considerably in recent years by the sequencing of the human genome and by structural studies, and has important implications for the future therapeutic potential of targeting this receptor family. This article aims to provide a comprehensive overview of the five main human GPCR families--Rhodopsin, Secretin, Adhesion, Glutamate and Frizzled/Taste2--with a focus on gene repertoire, general ligand preference, common and unique structural features, and the potential for future drug discovery.

1,247 citations


Journal ArticleDOI
TL;DR: How the signalling functions of bile acids can be exploited in the development of drugs for obesity, type 2 diabetes, hypertriglyceridaemia and atherosclerosis, as well as other associated chronic diseases such as non-alcoholic steatohepatitis are reviewed.
Abstract: Bile acids are increasingly being appreciated as complex metabolic integrators and signalling factors and not just as lipid solubilizers and simple regulators of bile-acid homeostasis. It is therefore not surprising that a number of bile-acid-activated signalling pathways have become attractive therapeutic targets for metabolic disorders. Here, we review how the signalling functions of bile acids can be exploited in the development of drugs for obesity, type 2 diabetes, hypertriglyceridaemia and atherosclerosis, as well as other associated chronic diseases such as non-alcoholic steatohepatitis.

1,107 citations


Journal ArticleDOI
TL;DR: This Review describes the growing body of data in favour of macrocyclic therapeutics, and demonstrates that this class of compounds can be both fully drug-like in its properties and readily prepared owing to recent advances in synthetic medicinal chemistry.
Abstract: Macrocyclic natural products have evolved to fulfil numerous biochemical functions, and their profound pharmacological properties have led to their development as drugs. A macrocycle provides diverse functionality and stereochemical complexity in a conformationally pre-organized ring structure. This can result in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular locations. Despite these valuable characteristics, and the proven success of more than 100 marketed macrocycle drugs derived from natural products, this structural class has been poorly explored within drug discovery. This is in part due to concerns about synthetic intractability and non-drug-like properties. This Review describes the growing body of data in favour of macrocyclic therapeutics, and demonstrates that this class of compounds can be both fully drug-like in its properties and readily prepared owing to recent advances in synthetic medicinal chemistry.

1,060 citations


Journal ArticleDOI
TL;DR: The applications of molecular Imaging in drug development are reviewed, highlighting successes and identifying key challenges that need to be addressed for successful integration of molecular imaging into the drug development process.
Abstract: Molecular imaging, which can allow the non-invasive monitoring of biological processes in living subjects, has the potential to enhance understanding of disease and drug activity in both preclinical and clinical drug studies, aiding effective translational research. Gambhir and colleagues review the applications of molecular imaging in drug development, and discuss challenges that need to be addressed to optimize its utility.

Journal ArticleDOI
TL;DR: There is growing evidence that the glutamatergic system is central to the neurobiology and treatment of mood disorders and exciting new prospects for the development of improved therapeutics for these devastating disorders are discussed.
Abstract: Mood disorders are common, chronic, recurrent mental illnesses that affect the lives of millions of individuals worldwide. To date, the monoaminergic systems (serotonergic, noradrenergic and dopaminergic) in the brain have received the greatest attention in neurobiological studies of mood disorders, and most therapeutics target these systems. However, there is growing evidence that the glutamatergic system is central to the neurobiology and treatment of these disorders. Here, we review data supporting the involvement of the glutamatergic system in mood-disorder pathophysiology as well as the efficacy of glutamatergic agents in mood disorders. We also discuss exciting new prospects for the development of improved therapeutics for these devastating disorders.

Journal ArticleDOI
TL;DR: Recent progress in the development of molecules that inhibit MET function are discussed and their application in a subset of human tumours that are potentially responsive to MET-targeted therapies is considered.
Abstract: The MET tyrosine kinase stimulates cell scattering, invasion, protection from apoptosis and angiogenesis, thereby acting as a powerful expedient for cancer dissemination. MET can also be genetically selected for the long-term maintenance of the primary transformed phenotype, and some tumours appear to be dependent on (or 'addicted' to) sustained MET activity for their growth and survival. Because of its dual role as an adjuvant, pro-metastatic gene for some tumour types and as a necessary oncogene for others, MET is a versatile candidate for targeted therapeutic intervention. Here we discuss recent progress in the development of molecules that inhibit MET function and consider their application in a subset of human tumours that are potentially responsive to MET-targeted therapies.

Journal ArticleDOI
TL;DR: The discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases is discovered.
Abstract: As our understanding of the endocannabinoids improves, so does the awareness of their complexity During pathological states, the levels of these mediators in tissues change, and their effects vary from those of protective endogenous compounds to those of dysregulated signals These observations led to the discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases When moving to the clinic, however, the pleiotropic nature of endocannabinoid functions will require careful judgement in the choice of patients and stage of the disorder for treatment

Journal ArticleDOI
TL;DR: The current state of development of HDAC therapeutics and their application for the treatment of human brain disorders such as Rubinstein–Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntington's disease and multiple sclerosis are summarized.
Abstract: Histone deacetylases (HDACs)--enzymes that affect the acetylation status of histones and other important cellular proteins--have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Pharmacological manipulations using small-molecule HDAC inhibitors--which may restore transcriptional balance to neurons, modulate cytoskeletal function, affect immune responses and enhance protein degradation pathways--have been beneficial in various experimental models of brain diseases. Although mounting data predict a therapeutic benefit for HDAC-based therapy, drug discovery and development of clinical candidates face significant challenges. Here, we summarize the current state of development of HDAC therapeutics and their application for the treatment of human brain disorders such as Rubinstein-Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntington's disease and multiple sclerosis.

Journal ArticleDOI
TL;DR: It is shown that a novel mechanism of intramyocardial fibroblast–cardiomyocyte communication that may prove to be a therapeutic target for the prevention of heart failure is discovered.
Abstract: For many years, the interleukin-1 receptor family member ST2 was an orphan receptor that was studied in the context of inflammatory and autoimmune disease. However, in 2005, a new cytokine — interleukin-33 (IL-33) — was identified as a functional ligand for ST2. IL-33/ST2 signalling is involved in T-cell mediated immune responses, but more recently, an unanticipated role in cardiovascular disease has been demonstrated. IL-33/ST2 not only represents a promising cardiovascular biomarker but also a novel mechanism of intramyocardial fibroblast–cardiomyocyte communication that may prove to be a therapeutic target for the prevention of heart failure.

Journal ArticleDOI
TL;DR: The p53 pathway has been shown to mediate cellular stress responses; p53 can initiate DNA repair, cell-cycle arrest, senescence and, importantly, apoptosis and this work focuses on how best to use knowledge of this pathway to tailor current therapies and develop novel ones.
Abstract: The p53 pathway has been shown to mediate cellular stress responses; p53 can initiate DNA repair, cell-cycle arrest, senescence and, importantly, apoptosis. These responses have been implicated in an individual's ability to suppress tumour formation and to respond to many types of cancer therapy. Here we focus on how best to use knowledge of this pathway to tailor current therapies and develop novel ones. Studies of the genetics of p53 pathway components - in particular p53 itself and its negative regulator MDM2 - in cancer cells has proven useful in the development of targeted therapies. Furthermore, inherited single nucleotide polymorphisms in p53 pathway genes could serve a similar purpose.

Journal ArticleDOI
TL;DR: Preclinical and clinical data on several compounds that inhibit the interaction between BCL-2 family members and their natural ligand, a helical peptide sequence known as the BH3 domain are reviewed, and four criteria that define antagonists of the B CL-2 protein family are recommended.
Abstract: Overexpression of members of the BCL-2 family of pro-survival proteins is commonly associated with unfavourable pathogenesis in cancer. The convergence of cytotoxic stress signals on the extended BCL-2 protein family provides the biological rationale for directly targeting this family to induce apoptotic cell death. Recently, several compounds have been described that inhibit the interaction between BCL-2 family members and their natural ligand, a helical peptide sequence known as the BH3 domain. Here, we review preclinical and clinical data on these compounds, and recommend four criteria that define antagonists of the BCL-2 protein family.

Journal ArticleDOI
TL;DR: The increased susceptibility of cancer cells to these compounds supports their potential use as cancer therapies, and the first generation of glycoside-based anticancer drugs are currently in clinical trials.
Abstract: Cardiac glycosides are a diverse family of naturally derived compounds that bind to and inhibit Na+/K+-ATPase. Members of this family have been in clinical use for many years for the treatment of heart failure and atrial arrhythmia, and the mechanism of their positive inotropic effect is well characterized. Exciting recent findings have suggested additional signalling modes of action of Na+/K+-ATPase, implicating cardiac glycosides in the regulation of several important cellular processes and highlighting potential new therapeutic roles for these compounds in various diseases. Perhaps most notably, the increased susceptibility of cancer cells to these compounds supports their potential use as cancer therapies, and the first generation of glycoside-based anticancer drugs are currently in clinical trials.

Journal ArticleDOI
TL;DR: The role of purinergic signalling in CNS disorders is reviewed, highlighting specificPurinergic receptor subtypes, most notably A2A, P2X4 and P2 X7, that might be therapeutically targeted for the treatment of these conditions.
Abstract: Purines have key roles in neurotransmission and neuromodulation, with their effects being mediated by the purine and pyrimidine receptor subfamilies, P1, P2X and P2Y. Recently, purinergic mechanisms and specific receptor subtypes have been shown to be involved in various pathological conditions including brain trauma and ischaemia, neurodegenerative diseases involving neuroimmune and neuroinflammatory reactions, as well as in neuropsychiatric diseases, including depression and schizophrenia. This article reviews the role of purinergic signalling in CNS disorders, highlighting specific purinergic receptor subtypes, most notably A(2A), P2X(4) and P2X(7), that might be therapeutically targeted for the treatment of these conditions.

Journal ArticleDOI
TL;DR: Accumulating evidence is reviewed suggesting that histamine indeed has roles in inflammation and immune function modulation in such diseases and a possible synergy between H1 and H4-receptor antagonists in targeting various inflammatory conditions is reviewed.
Abstract: Histamine has a key role in allergic inflammatory conditions. The inflammatory responses resulting from the liberation of histamine have long been thought to be mediated by the histamine H1 receptor, and H1-receptor antagonists--commonly known as antihistamines--have been used to treat allergies for many years. However, the importance of histamine in the pathology of conditions such as asthma and chronic pruritus may have been underestimated. Here, we review accumulating evidence suggesting that histamine indeed has roles in inflammation and immune function modulation in such diseases. In particular, the discovery of a fourth histamine receptor (H4) and its expression on numerous immune and inflammatory cells has prompted a re-evaluation of the actions of histamine, suggesting a new potential for H4-receptor antagonists and a possible synergy between H1 and H4-receptor antagonists in targeting various inflammatory conditions.

Journal ArticleDOI
TL;DR: The available data supporting the proposal that both TWEAK and Fn14 should be considered as potential targets for the development of novel therapeutics are summarized.
Abstract: TWEAK, a member of the tumour necrosis factor superfamily, is a multifunctional cytokine that acts on cells by binding to a small cell-surface receptor named Fn14. Here, Winkles summarizes the biology of the TWEAK–Fn14 axis and describes the recent evidence supporting the notion that this axis could be a therapeutic target for the treatment of cancer, chronic autoimmune diseases and acute ischaemic stroke. TWEAK is a multifunctional cytokine that controls many cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis and inflammation. TWEAK acts by binding to Fn14, a highly inducible cell-surface receptor that is linked to several intracellular signalling pathways, including the nuclear factor-κB (NF-κB) pathway. The TWEAK–Fn14 axis normally regulates various physiological processes, in particular it seems to play an important, beneficial role in tissue repair following acute injury. Furthermore, recent studies have indicated that TWEAK–Fn14 axis signalling may contribute to cancer, chronic autoimmune diseases and acute ischaemic stroke. This Review provides an overview of TWEAK–Fn14 axis biology and summarizes the available data supporting the proposal that both TWEAK and Fn14 should be considered as potential targets for the development of novel therapeutics.

Journal ArticleDOI
TL;DR: This Review provides an update on the current state-of-the-art for the various automated electrophysiology platforms that are now available and critically evaluates their impact in terms of ion-channel screening, lead optimization and the assessment of cardiac ion- channel safety liability.
Abstract: Ion channels represent highly attractive targets for drug discovery and are implicated in a diverse range of disorders, in particular in the central nervous and cardiovascular systems. Moreover, assessment of cardiac ion-channel activity of new chemical entities is now an integral component of drug discovery programmes to assess potential for cardiovascular side effects. Despite their attractiveness as drug discovery targets ion channels remain an under-exploited target class, which is in large part due to the labour-intensive and low-throughput nature of patch-clamp electrophysiology. This Review provides an update on the current state-of-the-art for the various automated electrophysiology platforms that are now available and critically evaluates their impact in terms of ion-channel screening, lead optimization and the assessment of cardiac ion-channel safety liability.

Journal ArticleDOI
TL;DR: Evidence is discussed supporting the idea that rather than being an exception, carrier-mediated and active uptake of drugs may be more common than is usually assumed and the implications for drug discovery and development are considered.
Abstract: It is generally thought that many drug molecules are transported across biological membranes via passive diffusion at a rate related to their lipophilicity. However, the types of biophysical forces involved in the interaction of drugs with lipid membranes are no different from those involved in their interaction with proteins, and so arguments based on lipophilicity could also be applied to drug uptake by membrane transporters or carriers. In this article, we discuss the evidence supporting the idea that rather than being an exception, carrier-mediated and active uptake of drugs may be more common than is usually assumed - including a summary of specific cases in which drugs are known to be taken up into cells via defined carriers - and consider the implications for drug discovery and development.

Journal ArticleDOI
TL;DR: The therapeutic rationale and potential for targeting the gut microbiota are described, strategies and systems-oriented technologies for achieving this goal are discussed, and efforts to understand the complex host–bacteria interactions are discussed.
Abstract: The significant involvement of the gut microbiota in human health and disease suggests that manipulation of commensal microbial composition through combinations of antibiotics, probiotics and prebiotics could be a novel therapeutic approach. A systems perspective is needed to help understand the complex host-bacteria interactions and their association with pathophysiological phenotypes so that alterations in the composition of the gut microbiota in disease states can be reversed. In this article, we describe the therapeutic rationale and potential for targeting the gut microbiota, and discuss strategies and systems-oriented technologies for achieving this goal.

Journal ArticleDOI
TL;DR: Current knowledge and data that strengthens sirtuins as a druggable set of enzymes for the treatment of age-associated diseases are discussed, including activation of SIRT1 in type 2 diabetes.
Abstract: Sirtuins post-translationally modulate the function of many cellular proteins that undergo reversible acetylation-deacetylation cycles, affecting physiological responses that have implications for treating diseases of ageing. Potent small-molecule modulators of sirtuins have shown efficacy in preclinical models of metabolic, neurodegenerative and inflammatory diseases, and so hold promise for drug discovery efforts in multiple therapeutic areas. Here, we discuss current knowledge and data that strengthens sirtuins as a druggable set of enzymes for the treatment of age-associated diseases, including activation of SIRT1 in type 2 diabetes.

Journal ArticleDOI
Avi Ashkenazi1
TL;DR: New molecular insights have inspired the development of pro-apoptotic receptor agonists (PARAs), including the recombinant human protein apoptosis ligand 2/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) and agonistic monoclonal antibodies to its signalling receptors.
Abstract: Each day, the human body eliminates billions of unwanted cells by apoptotic suicide. Apoptosis provides an important barrier against cancer; however, specific mutations enable some tumour cells to escape apoptotic death and become more malignant. Two signalling pathways initiate apoptosis: one acts through intracellular Bcl-2 proteins, the other through cell-surface pro-apoptotic receptors. New molecular insights have inspired the development of pro-apoptotic receptor agonists (PARAs), including the recombinant human protein apoptosis ligand 2/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) and agonistic monoclonal antibodies to its signalling receptors. Acting alone, or in concert with other agents, PARAs may overcome key apoptosis blocks and direct cancer cells to self-destruct.

Journal ArticleDOI
TL;DR: Some of the major applications of NMR in drug discovery, focusing on hit and lead generation, are highlighted, and a critical analysis of its current and potential utility is provided.
Abstract: In the past decade, the potential of harnessing the ability of nuclear magnetic resonance (NMR) spectroscopy to monitor intermolecular interactions as a tool for drug discovery has been increasingly appreciated in academia and industry. In this Perspective, we highlight some of the major applications of NMR in drug discovery, focusing on hit and lead generation, and provide a critical analysis of its current and potential utility.

Journal ArticleDOI
TL;DR: The N/OFQ-NOP system has been implicated in a wide range of biological functions, including pain, drug abuse, cardiovascular control and immunity as mentioned in this paper, and the current status of the very limited number of clinical trials.
Abstract: Identification of the enigmatic nociceptin/orphanin FQ peptide (N/OFQ) in 1995 represented the first successful use of reverse pharmacology and led to deorphanization of the N/OFQ receptor (NOP). Subsequently, the N/OFQ-NOP system has been implicated in a wide range of biological functions, including pain, drug abuse, cardiovascular control and immunity. Although this could be considered a hurdle for the development of pharmaceuticals selective for a specific disease indication, NOP represents a viable drug target. This article describes potential clinical indications and highlights the current status of the very limited number of clinical trials.

Journal ArticleDOI
TL;DR: This study is unaware of any recent Medline-indexed publications quantifying the globalization of biopharmaceutical clinical trials (BCTs; defined as trials assessing small-molecule pharmaceuticals and adjuvants, biologics and vaccines) based on publicly accessible data.
Abstract: Industry-sponsored clinical research has traditionally been carried out in relatively wealthy locations in North America, Western Europe and Oceania1. However, in recent years, a shift in clinical trials sponsored by the biopharma industry to so-called emerging regions, especially in Eastern European, Latin American and Asian countries, has been noted (for example, REFS 2–5). Reasons cited for this shift include the ability to reduce operational costs while recruiting a large number of patients in a timely manner; the establishment of contract research organizations focused on global clinical trials; the rapid pace of growth of market size, research capacity and regulatory authority in emerging regions; and the harmonization of guidelines for clinical practice and research1,2,4,6,7. It seems that these factors will continue to be prominent drivers of the globalization process, resulting in the solidification of trends and increased geographic dispersion of drug development operations6. Although these trends, and the associated regulatory, public health and economic implications, have been discussed qualitatively and extensively in the literature (for example, REFS 3,5,6,8), we are unaware of any recent Medline-indexed publications quantifying the globalization of biopharmaceutical clinical trials (BCTs; defined as trials assessing small-molecule pharmaceuticals and adjuvants, biologics and vaccines) based on publicly accessible data. This absence reflects in part historical difficulties in accessing comprehensive public data on the location of BCTs. However, owing to new mandates for clinical-trial registration from both the FDA and the International Committee of Medical Journal Editors9,10, there has recently been a substantial registration influx of ongoing and completed trials into ClinicalTrials.gov. As of January 2007, the site contains detailed descriptions of 36,249 recruiting and completed studies sponsored by the public and private sectors in more than 140 countries11. These data registry developments create the opportunity for a more detailed country and region-specific quantitative assessment of the globalization of BCTs, including clinical-trial capacity (the average number of sites per trial); trial density per population; size of trial; global span (regional versus global); and type of trial (early versus confirmatory versus post-marketing). Key results of such an analysis, conducted as described in Supplementary information S1 (box), are presented in FIG. 1 and TABLE 1, with extensive additional data available online (Supplementary information S2 (box), S3 (table), S4 (table), S5 (table), S6 (table)). This study has several limitations, especially concerning uncertainty about the evolving coverage ratio of ClinicalTrials. gov, incompleteness of the records of some trials and its US-centric nature. It is hoped that in the future, the public will have access to a database containing virtually complete coverage of global clinical development operations over time.