Streiner David L
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Can J Neurol Sci. 2007 Mar;34 Suppl 1:S37-41. doi: 10.1017/s0317167100005540.
Until recently, the gold standard for assessing the efficacy and effectiveness of new medications has been the placebo-control randomized clinical trial (RCT). However, there are serious ethical concerns about placing patients on a placebo when effective treatments exist. Further, if a new agent is tested only against a placebo, there is no guarantee that it is more effective, or even as effective, as an existing agent. For these and other reasons, ethicists and regulatory bodies have said that, under these circumstances, new drugs should be tested against an active agent. There are three types of such trials: superiority, equivalence, and non-inferiority. In superiority trials, the goal is to establish that the new drug is better (i.e., more effective, or with a more benign side-effect profile) than the standard. Because such trials require much larger sample sizes than placebo-control studies, and are rarely required to bring a drug onto market, they are rarely done. In equivalence trials, the aim is to show that the new and standard agents have similar degrees of effectiveness or adverse events. Due to sample size requirements, most studies of new drugs are non-inferiority trials, in which it is sufficient to demonstrate that the new drug is not significantly worse than the existing ones. However, there are methodological concerns with equivalence and non-inferiority trials, including (a) an inability to determine if the drugs were equally good or equally bad; (b) poorly executed trials with low power can be mistaken for "proving" equivalence or non-inferiority; (c) the equivalence interval is arbitrary; (d) successive non-inferiority trials may lead to a gradual reduction in effectiveness; and (e) often larger trials are necessary. The paper also discusses "add on trials." It is recommended that, even when existing drugs exist, trials should consist of at least three arms, one of which is a placebo. This paper briefly considers the ethics of placebo, and conditions are stated under which such studies can be conducted.
直到最近，评估新药疗效和有效性的金标准一直是安慰剂对照随机临床试验（RCT）。然而，当存在有效治疗方法时，让患者服用安慰剂存在严重的伦理问题。此外，如果一种新药仅与安慰剂进行测试，无法保证它比现有药物更有效，甚至不能保证它与现有药物效果相同。出于这些及其他原因，伦理学家和监管机构表示，在这种情况下，新药应与活性药物进行测试。这类试验有三种类型：优效性试验、等效性试验和非劣效性试验。在优效性试验中，目标是确定新药比标准药物更好（即更有效，或副作用更小）。由于这类试验所需样本量比安慰剂对照研究大得多，而且很少需要进行这类试验来使药物上市，所以很少进行。在等效性试验中，目的是表明新药和标准药物具有相似程度的有效性或不良事件。由于样本量要求，大多数新药研究是非劣效性试验，在这类试验中，足以证明新药不比现有药物差很多。然而，等效性和非劣效性试验存在方法学问题，包括：（a）无法确定药物是否同样好或同样差；（b）执行不力、效能低的试验可能被误认为“证明”了等效性或非劣效性；（c）等效区间是任意的；（d）连续的非劣效性试验可能导致有效性逐渐降低；（e）通常需要更大规模的试验。本文还讨论了“附加试验”。建议即使存在现有药物，试验至少应包括三个组，其中一组为安慰剂组。本文简要考虑了安慰剂的伦理问题，并说明了进行此类研究的条件。
