Developing and Testing Participant Information Leaflets (PILs) that Inform and do not Cause Harm (PrinciPILs)

我们进行了两项研究，证明有必要改善试验参与者被告知潜在试验益处和危害的方式。在第一个实验中，我们发现一半的试验参与者服用安慰剂（如糖丸），报告有负面的“副作用”。“五分之一服用安慰剂的参与者因干预”副作用而退出。“这有很多原因，包括负面的预期。试验参与者可能会被警告可能的副作用，以引起他们预期的方式，然后实际经历这种副作用。服用安慰剂的患者的负面副作用在疼痛相关，癌症和心理健康试验中更常见。例如，在一项阿司匹林或磺胺甲恶唑治疗胸痛的试验中，一些患者被告知这种药物可能会导致胃痛，而另一些则不会。被告知经历胃痛的患者因胃痛而退出试验的可能性是其他患者的六倍。在我们的第二项研究中，我们发现患者信息传单（PIL）并不总是告诉试验参与者他们理解或想要什么。我们研究了33个PIL，发现关于伤害的信息共享方式似乎没有遵循任何逻辑模式。他们中的大多数人对危害的信息比好处多，有些人根本没有提到好处。这似乎是因为研究人员认为，作为知情同意的一部分，他们必须披露每一个问题。分享参与试验的危害信息的方式实际上会造成伤害。因此，如果以一种可怕的方式（特别是如果没有提到益处）介绍试验危害的信息会造成不必要的伤害，则可能是不道德的。患者代表和其他利益相关者协助制定PIL。然而，目前还没有具体的指导方针，说明他们应该如何反映潜在的利益和危害，以避免不必要地担心试验参与者。我们建议开发一种方法，用于在PIL中呈现益处和危害信息，该方法严格考虑患者，医生和研究伦理委员会成员的意见。然后，我们将测试它们是否减少副作用并提高试验招募率。我们将分五步实现目标。我们将对利益相关者进行调查，以了解他们对如何在PIL中传达有关试验参与危害和获益的信息的看法。信息应提供事实，同时不造成信息诱导的伤害。利益相关者将包括患者、研究伦理委员会成员、临床医生、医学法律专家、监管机构和临床试验管理人员。他们将根据我们的背景研究确定为对信息引起的伤害敏感的条件之一的经验进行选择（见“目标”）。然后，我们将与我们的咨询小组合作，从利益相关者的访谈中确定原则。该小组将包括申请人，病人代表和REC成员。使用这些原则，我们将设计五个试验的PIL。我们称之为“原则”。4.然后，我们将在试验中比较PrinciPIL与标准PIL。我们将测试暴露于PrinciPIL的患者是否具有较少的负面副作用。最后，我们将制定并向相关利益相关者传播指南，以便提供有关潜在试验或治疗益处和危害的信息的人可以生成PrinciPIL。我们研究的主要成果将是关于使用PrinciPIL的效果的报告和设计它们的指南。我们希望我们的研究结果在试验之外和临床实践中是有用的，临床医生也需要向患者提供有关干预措施的危害和益处的信息。

We conducted two studies that demonstrated the need to improve the way trial participants are told about potential trial benefits and harms. In the first, we found that half of the participants in trials who take a placebo treatment (like a sugar pill) report having a negative 'side effect.' 1 in 5 of the participants who took a placebo dropped out due to an intervention 'side effect.' There are many reasons for this, including negative expectations. A trial participant might be warned about a possible side effect in a way that caused them to expect, and then actually experience this side effect. Negative side effects among patients taking placebos were more common in pain-related, cancer, and mental health trials. For example, in a trial of aspirin or sulfinpyrazone for treating chest pain, some patients were told the drug might cause stomach pain, and others were not. The patients who were told about experiencing stomach pain were six times more likely to withdraw from the trial because of stomach pain. In our second study, we found that patient information leaflets (PILs) do not always tell trial participants what they understand or want. We looked at 33 PILs and found that the way information about harms was shared did not seem to follow any logical pattern. Most of them had more information about harms than benefits, and some did not mention benefits at all. This seems to be because researchers feel they have to disclose every problem as part of ethical informed consent.Our background research also highlighted an ethical issue. The way in which information about harms of participating in trials is shared can actually cause harm. Therefore, presenting information about trial harms in a scary way (especially if benefits are not mentioned) could be unethical if it causes unnecessary harm.Patient representatives and other stakeholders assist in developing PILs. However, there is currently no guidance specifically on how they should reflect about the way potential benefits and harms are presented to avoid worrying trial participants unnecessarily. We propose to develop a method for presenting benefit and harm information within PILs that rigorously considers patient, doctor and research ethics committee member views. We will then test to see whether they reduce side effects and improve trial recruitment rates. We will achieve our aim in five steps.1. We will survey stakeholders to understand their views about how the information about trial participation harms and benefits should be communicated in PILs. The information should provide facts and at the same time not cause 'information-induced harm.' The stakeholders will include patients, research ethics committee members, clinicians, medico-legal experts, regulators, and clinical trial managers. They will be chosen based on their experience with one of the conditions that our background research identified as being sensitive to information-induced harm (see 'Objectives').2. We will then work with our advisory group to identify principles from the stakeholder interviews. The group will include applicants, patient representatives, and REC members.3. Using the principles, we will design PILs for five trials. We will call these 'PrinciPILs'.4. We will then compare PrinciPILs with standard PILs in the trials. We will test whether patients exposed to PrinciPILs had fewer negative side effects.5. Finally, we will develop and disseminate guidance to relevant stakeholders so that those providing information about potential trial or treatment benefits and harms can generate PrinciPILs.The main outputs from our study will be a report on effects of using PrinciPILs and guidelines designing them. We expect our findings will be useful outside trials and in clinical practice, where clinicians also need to present information about harms and benefits of interventions to patients.