Department of Environmental Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA 01003, USA.
University of Maine, 5728 Fernald Hall, Room 201, Orono, ME 04469, USA.
Ageing Res Rev. 2023 Sep;90:102028. doi: 10.1016/j.arr.2023.102028. Epub 2023 Aug 6.
The present paper identifies a critical factor that leads to false negative results (i.e., failing to indicate efficacy when beneficial results did occur) in randomized human drug trials. The paper demonstrates that human performance can only be enhanced by a maximum of 30-60% as described by the hormetic dose response which defines the limits of biological plasticity. However, human epidemiological/clinical trials typically contain such extensive variability that often requires responses greater than 2-3 times control group responses to show statistical significance. Thus, many potentially beneficial agents may be missed because the clinical trial fails to recognize and take into consideration the limits of biological plasticity. The paper proposes that this hormesis-biological plasticity-clinical trial conundrum can be addressed successfully via the use of a weight-of-evidence methodology similar to that used by regulatory agencies such as EPA in environmental assessment of chemical toxicity.
本文确定了一个导致随机人体药物试验出现假阴性结果（即当出现有益结果时未能表明疗效）的关键因素。本文表明，正如 hormetic 剂量反应所定义的那样，人体的表现只能最多提高 30-60%，这界定了生物可塑性的极限。然而，人体流行病学/临床试验通常包含如此广泛的变异性，通常需要比对照组高 2-3 倍的反应才能显示出统计学意义。因此，许多潜在的有益药物可能会被遗漏，因为临床试验未能认识到并考虑到生物可塑性的极限。本文提出，通过使用类似于 EPA 等监管机构在化学毒性环境评估中使用的证据权重方法，可以成功解决这种 hormesis-生物可塑性-临床试验难题。
