MICA: Early Phase Dose-finding Trials: Development of reporting guidance to improve knowledge transfer

临床试验是一项研究，涉及患者或健康志愿者，旨在测试一种新的治疗方法是否安全，是否比目前的治疗方法更好。临床试验分为阶段（或阶段），研究人员旨在回答每个阶段的不同问题。其中最早的阶段，即第一阶段，旨在测试治疗是否安全，调查副作用，并为进一步测试推荐治疗剂量。I期试验涉及少量参与者，他们可能是健康志愿者或患者。在I期试验中，第一组参与者接受低剂量的治疗，如果证明是安全的，没有许多副作用，下一组参与者接受更高剂量的治疗。进一步的参与者组被招募;随着剂量的增加，每个连续的组都被提高，直到达到具有太多负面副作用的剂量。在给予治疗之前，应仔细决定是否给予患者相同、更高或更低剂量的治疗。这些试验被称为“剂量递增”或“剂量探索”试验。一旦临床试验完成，结果将向临床研究界和公众报告。为了确保这些报告的可靠性，并有助于进一步的研究，一套指南的重要项目，报告试验的统一标准（或简称CONSORT）已出版。它规定了作者报告试验设计、分析和解释的标准方式，并有助于促进透明的报告。最初的CONSORT指南是为特定类型的试验制定的，其设计特征通常与剂量探索试验不同。这一点很重要，因为目前I期试验的试验报告经常遗漏有关其设计和实施方式的重要信息，这可能使读者难以解释和衡量试验的有效性。这浪费了时间和资源，但更重要的是，可能会不道德地使参与者面临无效甚至有害的干预。在I期试验中做出最好的决定，是否给患者相同的剂量，或者更高或更低的剂量，是试验成功的关键。在过去的25年里，用于指导这些决策的统计方法有了显著的进步，因此可以进行更安全的试验，获得更可靠的结果。但这些方法通常很复杂，而且有额外的透明度和报告要求。为了解决这些问题，我们将开发CONSORT指南的“扩展”，该指南适用于不同疾病的所有早期剂量探索设计。主要的CONSORT声明现已扩展到其他7个设计领域，主要是在后期试验中（www.consort-statement.org/extensions）。剂量探索试验的CONSORT扩展早就应该进行了。为了制定一个国际公认的报告此类试验的方法，我们汇集了一个多学科的国际专家团队，他们在学术机构或制药行业工作，负责设计，运行和报告早期试验，并在制定试验报告指南方面具有专业知识。最后，为了确保开发的CONSORT扩展将被广泛采用，我们将在整个研究过程中涉及关键群体：试验社区，期刊编辑（发表关于剂量探索试验的文章），同行评审员（评估研究论文），监管机构，患者和公众。我们将在相关会议上以及向当地/国家患者和公众参与（PPI）团体宣传我们的成果，并将利用社交媒体提高认识。我们将举办实践研讨会，强调常见的报告缺陷以及如何使用新指南。我们将与我们的PPI代表共同制作两份非专业文件，以有效地参与，参与并告知患者和公众这项工作的重要性。

Clinical trials are research studies involving patients or healthy volunteers which aim to test whether a new treatment is safe and 'better' than current treatment. Clinical trials are grouped into stages (or phases) and researchers aim to answer different questions at each of the phases. The earliest of these, Phase I, aims to test whether a treatment is safe, to investigate side effects and to and to recommend a dose of the treatment for further testing. Phase I trials involve small numbers of participants who may be healthy volunteers or patients. The first group of participants in a phase I trial are given a low dose of treatment and if shown to be safe and without many side effects, the next group of participants are given a higher dose. Further groups of participants are enrolled; with the dose, being raised for each successive group until a dose is reached that has too many negative side effects. The decision whether to give patients the same, a higher, or lower dose of treatment is carefully made before the treatment is given. These trials are called "dose-escalation" or "dose-finding" trials.Once a clinical trial is complete, the results are reported to the clinical research community and to the public. To make sure that these reports are reliable and helpful for further research, a set of guidelines of the important items to be reported, Consolidated Standards of Reporting Trials (or CONSORT for short) have been published. It sets out a standard way for authors to report how the trial is designed, analysed and interpreted and has been instrumental in promoting transparent reporting. The original CONSORT guidelines were developed for specific types of trials and their design features often differ from dose-finding trials. This is important as currently trial reports of Phase I trials often miss out important information about how they were designed and conducted, which can make it difficult for the reader to interpret and gauge the validity of the trials. This wastes time and resources, but more importantly, may unethically expose participants to ineffective or even harmful interventions. Making the best decisions in a Phase I trial, on whether to give a patient the same dose, or a higher or lower dose, is key to the success of the trial. The statistical methods used to guide these decisions have advanced significantly over the past 25 years, so that safer trials with more reliable results can be conducted. But these methods are often complex, and have additional transparency and reporting demands.To address these problems, we will develop an 'extension' to the CONSORT guidelines, which is relevant to all early phase dose-finding designs in different diseases. The main CONSORT Statement has now been extended in 7 other design areas, primarily in later phase trials (www.consort-statement.org/extensions). A CONSORT extension for dose-finding trials is long overdue. To develop an internationally agreed way to report such trials, we have brought together a multi-disciplinary, international team of experts in the design, running and reporting of early phase trials who work in academic institutions or pharmaceutical industry, and those with expertise in developing reporting guidelines of trials. Finally, to ensure that the developed CONSORT extension will be widely adopted, we will involve key groups throughout this research: the trial community, journal editors (who publish articles on dose-finding trials), peer reviewers (who assess research papers), regulators, patients and the public. We will publicise our outputs at relevant meetings and to local/national Patient and Pubic Involvement (PPI) groups, and will use social media to raise awareness. We will conduct practical workshops, highlighting common reporting flaws and how to use the new guideline. We will co-produce two lay papers with our PPI representative to effectively involve, engage and inform patients and the public about the importance of this work.