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

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.

Presentation of potential trial participation harms and benefits in PILs varies, with trial benefits sometimes not being mentioned. This can waste scarce resources (with every PI having to negotiate their own method) and can cause information-induced adverse events ('nocebo effects'). Our aim is to develop and test PILs that help solve these problems. This will be achieved in 5 steps:

1. Obtaining stakeholder views: We will obtain participant, clinician, ethicist, medico-legal expert, research nurse, and trial manager views about how to balance information about trial harms and benefits within PILs.
2. Identify Principles: Based on (1), develop principles to guide PIL design.
3. Development: Based on (2), design PILs for three trials. We will call these 'PrinciPILs'.
4. Testing: Set up five studies within a trial (SWATs). The SWATs will involve randomising participants to receive 'standard' PIL (developed by host trialists), or a PrinciPIL. We will analyse early results (recruitment and retention rates, AEs) ease of recruiting host trials; facilitators and barriers to PrinciPIL-testing and acceptance. We will also set up an infrastructure for embedding results of future PrinciPIL SWATs in a meta-analysis, should this be required.
5. Generating guidance and a resource for designing and testing PrinciPILs: We will produce guidance for producing and testing PrinciPILs. We aim for this resource to be become part of the package supported by the HRA and therefore may result in changes to their templates for PILs.

Importantly, PrinciPILs are valuable even if they do not reduce information induced AEs. This is because PrinciPILs will be generated using the transparent methodology described above, whereas the way in which trial benefits and harms are presented in current PILs which do not seem to be based on an ethically justified rationale.