Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Blood. 2010 Oct 7;116(14):2420-8. doi: 10.1182/blood-2010-05-285387. Epub 2010 Jun 10.
Drugs introduced over the past 25 years have benefitted many patients with acute myeloid leukemia (AML) and provided cure for some. Still, AML remains difficult to treat, and most patients will eventually die from their disease. Therefore, novel drugs and drug combinations are under intense investigation, and promising results eagerly awaited and embraced. However, drug development is lengthy and costs are staggering. While the phase 1-phase 2-phase 3 sequence of clinical drug testing has remained inviolate for decades, it appears intrinsically inefficient, and scientific flaws have been noted by many authors. Of major concern is the high frequency of false-positive results obtained in phase 2 studies. Here, we review features of phase 2 trials in AML that may contribute to this problem, particularly lack of control groups, patient heterogeneity, selection bias, and choice of end points. Recognizing these problems and challenges should provide us with opportunities to make drug development more efficient and less costly. We also suggest strategies for trial design improvement. Although our focus is on the treatment of AML, the principles that we highlight should be broadly applicable to the evaluation of new treatments for a variety of diseases.
在过去的 25 年中，有许多新药被引入并应用于治疗急性髓系白血病（AML），并为部分患者带来了治愈的希望。然而，AML 的治疗仍然具有挑战性，大多数患者最终仍会死于该疾病。因此，新型药物和药物组合正在被深入研究，人们期待并欢迎有前景的研究结果。然而，药物研发过程漫长且成本高昂。尽管临床药物测试的 1 期-2 期-3 期序列在过去几十年中一直保持不变，但它似乎内在效率低下，许多作者已经注意到了科学缺陷。主要关注的问题是在 2 期研究中获得的高假阳性结果的频率。在这里，我们回顾了 AML 中可能导致这一问题的 2 期试验的特征，特别是缺乏对照组、患者异质性、选择偏倚和终点选择。认识到这些问题和挑战应该为我们提供机会，使药物开发更高效、成本更低。我们还提出了改进试验设计的策略。尽管我们的重点是 AML 的治疗，但我们强调的原则应该广泛适用于评估各种疾病的新治疗方法。
