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

我们进行了两项研究，证明有必要改善告知试验参与者潜在试验益处和危害的方式。在第一个实验中，我们发现，在接受安慰剂治疗(如糖丸)的试验参与者中，有一半的人报告了负面的“副作用”。在服用安慰剂的参与者中，有五分之一的人因为干预的“副作用”而退出了治疗。造成这种情况的原因有很多，包括负面预期。试验参与者可能会被警告可能的副作用，使他们预料到，然后实际体验到这种副作用。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为常见。例如，在一项阿司匹林或磺胺吡喃酮治疗胸痛的试验中，一些患者被告知这种药物可能会导致胃痛，而另一些患者则不会。被告知经历胃痛的患者因胃痛而退出试验的可能性是对照组的六倍。在我们的第二项研究中，我们发现患者信息传单(PILS)并不总是告诉试验参与者他们理解或想要什么。我们查看了33个皮尔斯，发现关于伤害的信息分享的方式似乎没有遵循任何逻辑模式。他们中的大多数人更多的是关于伤害的信息，而不是好处，有些人根本没有提到好处。这似乎是因为研究人员觉得他们必须披露每一个问题，作为道德知情同意的一部分。我们的背景研究也强调了一个道德问题。分享有关参与试验的危害的信息的方式实际上可能会造成危害。因此，以一种可怕的方式提供关于试验危害的信息(特别是在没有提到好处的情况下)可能是不道德的，如果它造成了不必要的伤害。患者代表和其他利益相关者协助制定PILS。然而，目前还没有具体的指导意见，说明它们应该如何反映潜在的益处和危害的呈现方式，以避免不必要地令试验参与者担忧。我们建议开发一种在PILS中显示益处和危害信息的方法，该方法严格考虑患者、医生和研究伦理委员会成员的意见。然后我们将进行测试，看看它们是否减少了副作用，并提高了试用期招聘率。我们将分五步实现我们的目标。我们将对利益相关者进行调查，以了解他们对参与试验的危害和好处的信息应如何在PILS中传达的看法。这些信息应该提供事实，同时不会造成“信息引发的伤害”。利益相关者将包括患者、研究伦理委员会成员、临床医生、法医专家、监管机构和临床试验经理。他们将根据他们对我们的背景研究确定的对信息引起的伤害敏感的条件之一的经验来选择(见“目标”)。然后，我们将与我们的顾问小组合作，从与利益相关者的面谈中确定原则。该小组将包括申请者、患者代表和REC成员。根据这些原则，我们将为五个试验设计PILS。我们将这些称为‘PrincPILs’。然后我们将在试验中将PrincPILs与标准PILs进行比较。我们将测试暴露于PrincPILs的患者是否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分发指导意见，以便那些提供有关潜在试验或治疗益处和危害的信息的人能够生成PrincPILs。我们研究的主要成果将是一份关于使用PrincPILs的效果的报告和设计这些PILs的指南。我们希望我们的发现将在外部试验和临床实践中有用，临床医生也需要向患者提供关于干预的危害和好处的信息。

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.