Novartis Pharma AG, One Health Plaza, East Hanover, NJ 07936-1080, USA.
Ann Ist Super Sanita. 2011;47(1):8-13. doi: 10.4415/ANN_11_01_03.
Pharmaceutical innovation is increasingly risky, costly and at times inefficient, which has led to a decline in industry productivity. Despite the increased investment in R&D by the industry, the number of new molecular entities achieving marketing authorization is not increasing. Novel approaches to clinical development and trial design could have a key role in overcoming some of these challenges by improving efficiency and reducing attrition rates. The effectiveness of clinical development can be improved by adopting a more integrated model that increases flexibility and maximizes the use of accumulated knowledge. Central to this model of drug development are novel tools, including modelling and simulation, Bayesian methodologies, and adaptive designs, such as seamless adaptive designs and sample-size re-estimation methods. Applications of these methodologies to early- and late-stage drug development are described with some specific examples, along with advantages, challenges, and barriers to implementation. Because they are so flexible, these new trial designs require significant statistical analyses, simulations and logistical considerations to verify their operating characteristics, and therefore tend to require more time for the planning and protocol development phase. Greater awareness of the distinct advantages of innovative designs by regulators and sponsors are crucial to increasing the adoption of these modern tools.
制药创新的风险越来越大，成本越来越高，有时效率也不尽如人意，这导致了行业生产力的下降。尽管行业在研发方面的投入不断增加，但获得营销授权的新分子实体的数量并未增加。通过采用更具创新性的临床试验设计方法，有可能通过提高效率和降低淘汰率来克服其中的一些挑战。通过采用更具灵活性和最大限度利用积累知识的综合模型，可以提高临床开发的效果。新药研发模式的核心是新工具，包括建模和模拟、贝叶斯方法以及适应性设计，例如无缝适应性设计和样本量重新估计方法。本文描述了这些方法在药物开发的早期和晚期阶段的应用，并举例说明了它们的优势、挑战和实施障碍。由于这些新的试验设计非常灵活，因此需要进行大量的统计分析、模拟和后勤考虑，以验证其运行特性，因此通常需要更多的时间来进行规划和方案制定阶段。监管机构和赞助商对创新设计的明显优势有更深入的了解，对于增加对这些现代工具的采用至关重要。
