Lockhart Brian P, Walther Bernard
Directeur de Division, Pharmacologie et Physiopathologie Moléculaires, Institut de Recherches Servier, 78290 Croissy-sur-Seine, France.
Med Sci (Paris). 2009 Apr;25(4):423-30. doi: 10.1051/medsci/2009254423.
Despite continued increase in global Pharma R & D expenditure, the number of innovative drugs obtaining market approval has declined since 1994. The pharmaceutical industry is now entering a crucial juncture where increasing rates of attrition in clinical drug development as well as increasing development timelines are impacted by external factors such as intense regulatory pricing and safety pressures, increasing sales erosion due to generics, as well as exponential increases in the costs of bringing a drug to market. Despite these difficulties, numerous opportunities exist such as multiple unmet medical needs, the increasing incidence of certain diseases such as Alzheimer's disease, cancer, diabetes and obesity due to demographic changes, as well as the emergence of evolving markets such as China, India, and Eastern Europe. Consequently, Pharma is now responding to this challenge by improving both the productivity and the innovation in its drug discovery and development pipelines. In this regard, the advent of new technologies and expertise such as genomics, proteomics, structural biology, and molecular informatics in an integrated systems biology approach also provides a powerful opportunity for Pharma to address some of these difficulties. The key features behind this new strategy imply a discovery process based on an improved understanding of the molecular mechanism of diseases and drugs, translational research that places the patient at the center of the research process, and the application of biomarkers throughout the discovery and development phases. Moreover, new paradigms are required to improve target validation and develop more predictive cellular and animal models of human pathologies, a greater capacity in informatics-based analysis, and, consequently, a greater access to the vast sources of accumulating biological data and its integrated analysis. In the present review, we will address some of these issues and in particular emphasize how the application of biomarkers could potentially lead to improved productivity, quality, and innovation in drug discovery and ultimately better and safer medicines with improved therapeutic efficacy in specific pathologies for targeted patients.
尽管全球制药研发支出持续增加，但自1994年以来，获得市场批准的创新药物数量却有所下降。制药行业如今正进入一个关键阶段，临床药物开发中日益增加的损耗率以及不断延长的开发时间线受到多种外部因素的影响，如严格的监管定价和安全压力、仿制药导致的销售侵蚀加剧，以及将药物推向市场的成本呈指数级增长。尽管存在这些困难，但仍有众多机会，比如存在多种未满足的医疗需求、由于人口结构变化导致某些疾病（如阿尔茨海默病、癌症、糖尿病和肥胖症）的发病率不断上升，以及中国、印度和东欧等新兴市场的出现。因此，制药行业目前正通过提高药物发现和开发流程的生产率与创新能力来应对这一挑战。在这方面，基因组学、蛋白质组学、结构生物学和分子信息学等新技术和专业知识以综合系统生物学方法的出现，也为制药行业解决其中一些难题提供了强大机遇。这一新策略背后的关键特征意味着发现过程基于对疾病和药物分子机制的更好理解、将患者置于研究过程中心的转化研究，以及在整个发现和开发阶段应用生物标志物。此外，需要新的范式来改进靶点验证并开发更具预测性的人类病理学细胞和动物模型，提高基于信息学的分析能力，从而更广泛地获取大量不断积累的生物数据及其综合分析结果。在本综述中，我们将探讨其中一些问题，尤其强调生物标志物的应用如何有可能提高药物发现的生产率、质量和创新能力，并最终为特定病理的目标患者带来疗效更佳、更安全的药物，且具有更高的治疗效果。
