Open-label extension studies - Do they provide meaningful information on the safety of new drugs?
Open-label extension studies - Do they provide meaningful information on the safety of new drugs?
复制标题
DOI：
10.2165/00002018-200730020-00001
复制
发表时间：
2007-01-01
期刊：
影响因子：
4.2
通讯作者：
Williams, Kenneth M.
中科院分区：
文献类型：
--
作者：
Day, Richard O.;Williams, Kenneth M.
近年来，正在进行的开放标签扩展研究的数量大幅增加。通常很难区分这些扩展研究和之前的双盲对照研究。如果主要是为了收集更多的新药暴露患者年，以了解其安全性并获得对其安全性的信心，开放标签扩展研究可以在药物开发和治疗中发挥有用和合法的作用。然而，只有在开放标签扩展研究的设计、执行、分析和报告合格的情况下，才可能发生这种情况。开放标签扩展研究中积累的大部分价值来自于对不良反应预期发生率的改进，这些不良反应很可能已经被确定为临床前和临床试验项目的一部分。我们仍然必须严重依赖于上市后安全监测系统来提醒我们注意B类（不可预测的）不良反应，因为开放标签扩展研究不太可能提供关于这些类型的通常严重和相对罕见的不良反应的有用信息，需要随机分配到试验组和对照组中，以产生关于预期不良反应或A类不良反应的精确发生率数据。开放标签扩展研究可能会增加对发病率的信心;然而，由于这些研究基本上是无对照和有偏倚的，因此数据没有很大价值。这些措施包括参与III期关键性试验的志愿者持续获得有效但无法获得的药物。然而，对于招募对先前治疗的反应不确定的患者的适当性存在未被认识到的伦理问题，这主要是因为在进入开放标签扩展研究时，先前随机、双盲、对照试验中的治疗分配尚未被揭示。开放标签扩展研究的负面方面围绕其作为营销工具的使用，因为他们为这种药物建立了一个市场，并从消费者和他们的医生那里产生了获得补贴的压力。消费者、开展这些研究的机构和研究伦理委员会在支持此类研究之前，需要确信开放标签扩展研究及其执行的动机和质量。开放标签扩展研究在新药临床开发中确实具有合法但有限的地位。对这些研究的负面看法的出现是因为对这种类型研究的可接受的理论基础的歪曲，以及未能认识到（或披露）其设计中固有的弱点所造成的局限性。在合理控制的情况下增加新药的人体暴露量以增加对药物安全性的信心是开放标签扩展研究的可接受理由，也是增加对新药安全性特征的了解的有用活动。然而，这一目标越来越多地通过开放标签扩展研究以外的方式实现。
The number of open-label extension studies being performed has increased enormously in recent years. Often it is difficult to differentiate between these extension studies and the double-blind, controlled studies that preceded them. If undertaken primarily to gather more patient-years of exposure to the new drug in order to understand and gain confidence in its safety profile, open-label extension studies can play a useful and legitimate role in drug development and therapeutics. However, this can only occur if the open-label extension study is designed, executed, analysed and reported competently. Most of the value accrued in open-label extension studies is gained from a refinement in the perception of the expected incidence of adverse effects that have most likely already been identified as part of the preclinical and clinical trial programme. We still have to rely heavily on post-marketing safety surveillance systems to alert us to type B (unpredictable) adverse reactions because open-label extension studies are unlikely to provide useful information about these types of often serious and relatively rare adverse reactions.Random allocation into test and control groups is needed to produce precise incidence data on pharmacologically expected, or type A, adverse effects. Some increased confidence about incidence rates might result from the open-label extension study; however, as these studies are essentially uncontrolled and biased, the data are not of great value.Other benefits have been proposed to be gained from open-label extension studies. These include ongoing access to an effective but otherwise unobtainable medicine by the volunteers who participated in the phase III pivotal trials. However, there are unappreciated ethical issues about the appropriateness of enrolling patients whose response to previous treatment is uncertain, largely because treatment allocation in the preceding randomised, double-blind, controlled trial has not been revealed at the time of entry into the open-label extension study.Negative aspects of open-label extension studies revolve around their use as a marketing tool, as they build a market for the drug and generate pressure for subsidised access to the drug from consumers and their physicians. Consumers, institutions where these studies are conducted and research ethics committees need to be convinced of the motives, as well as the quality, of the open-label extension study and its execution before supporting such studies.Open-label extension studies do have a legitimate but limited place in the clinical development of new medicines. The negative perceptions about these studies have arisen because of perversion of acceptable rationales for this type of study and a failure to recognise (or disclose) the limitations resulting from the inherent weaknesses in their design. Increased human exposure to a new medicine under reasonably controlled circumstances to increase confidence in the safety of the medicine is an acceptable rationale for an open-label extension study, and a useful activity to increase the knowledge of the safety profile of a new medicine. However, this goal is increasingly being achieved by means other than open-label extension studies.