Developing evidence-based guidelines for describing potential benefits and harms within patient information leaflets/sheets (PILs) that inform and do not cause harm (PrinciPILs).

Abstract

BACKGROUND

Variation in the way information about potential trial intervention benefits and harms is conveyed within patient information leaflets can cause avoidable information-induced ('nocebo') harm, research waste, and may be unethical.

OBJECTIVES

1. To develop stakeholder-informed principles to guide how to describe information about potential trial intervention benefits and harms within patient information leaflets. 2. To test whether using these principles are feasible for testing in trials that measure whether they improve recruitment and adverse event rates. 3. To develop and disseminate guidance on how to implement the principles.

METHODS

We used a mixed methodology consisting of three work packages. Work package 1 involved a modified Delphi survey and consensus meeting to develop the principles for harmonising the way information regarding potential benefits and harms are shared. Work package 2 involved testing whether the principles could be used to transform existing patient information leaflets by recruiting host trials to compare standard patient information leaflets with patient information leaflets developed using the principles 'principled patient information leaflets'. We also set up an infrastructure to test whether they could reduce variation, impact trial recruitment and reduce reported adverse events. Work package 3 involved developing and disseminating guidance for using the principles.

RESULTS

For work package 1, 250 participants completed the Delphi survey and 7 principles were agreed upon: (1) all potential intervention harms should be listed, (2) potential harms should be separated into 'serious' and 'less serious', (3) if not all potential harms are known, this needs to be explicitly stated, (4) all potential benefits should be listed, (5) potential benefits and harms associated with trial participation need to be compared with those associated with non-participation, (6) suitable visual representations should be added where appropriate, and (7) information about potential benefits and harms should not be separated by more than one page. For work package 2, we developed principled patient information leaflets for five host trials and interviewed two members of each host trial team. Two host trials agreed to compare the patient information leaflets with principled patient information leaflets using Studies Within a Trial, and we published a protocol for a meta-analysis that will synthesise the results. For work package 3, 25 participants attended a hybrid workshop and recommended that researchers and Research Ethics Committee members should use the principles to design and evaluate patient information leaflets. We produced a guidance booklet and website, which are currently being used by some Health Research Authority Research Ethics Committees.

CONCLUSIONS

A strong consensus was reached regarding seven principles that can harmonise the way information about the potential benefits and harms of trial interventions is shared. The principles are likely to reduce research waste and avoidable information-induced harm, and may enhance clinical trial ethics.

LIMITATIONS

Due to COVID-19, the National Institute for Health and Care Research review of ongoing trials that resulted in funding termination for several trials, and highly pressured trial staff with limited capacity to add Studies Within a Trial to their trials, we had to modify our second objective. Whereas we initially intended to actually conduct the Studies Within a Trial, we replaced this with: a protocol for a meta-analysis of Studies Within a Trial, additional research on the need to reduce variation, additional dissemination work, and a paper on the ethical requirement to mention potential benefits and harms of trial interventions in patient information leaflets.

FUTURE WORK

Future work could apply these results to explore how to harmonise the way potential benefits and harms are shared during verbal conversations between researchers and patients during the informed consent process.

FUNDING

This award was funded by the Medical Research Council and the National Institute for Health and Care Research (NIHR) Better Methods, Better Research programme (MRC Award Reference: MR/V020706/1) and is published in full in Health Technology Assessment; Vol. 29, No. 43.

Plain language summary

Researchers sometimes fail to tell participants about the possible benefits of taking a trial treatment. However, participants are almost always told about the potential harms. This imbalance can cause people to develop overly negative beliefs about treatments, which can have negative consequences. For example, worrying about a headache or nausea can cause mild headaches or nausea. Negative effects caused by negative beliefs are called ‘nocebo’ effects. The opposite can also occur. W ithout enough information, participants can develop overly positive expectations about treatment benefits. We investigated how to ensure that the information shared with participants about potential benefits and harms is understandable, honest, ethical and balanced. We surveyed a variety of stakeholders to understand what information about the possible benefits and harms they would like to know. We focused on the written information provided within patient information leaflets. The stakeholders included trial participants, ethics committee members, researchers, trial nurses, industry representatives and legal experts. Our survey identified a widespread agreement on seven principles to use when writing about possible benefits and harms within patient information leaflets: All potential intervention harms should be listed. Potential harms should be separated into ‘serious’ and ‘less serious’ categories. If all potential harms are not known, this should be explicitly stated. All potential benefits should be listed. The potential benefits and harms associated with participation need to be compared with those associated with non-participation. Suitable visual representations should be added where appropriate. The information about potential benefits and harms should be presented in proximity to one another. We then developed user-friendly guidance so that the principles could be easily used. We also laid the foundation for future tests on whether these principles reduce ‘nocebo’ effects. Researchers and ethics committees will now have clear guidance to follow when they write about possible benefits and harms within patient information leaflets. This will save time and make patient information leaflets more ethical. The principles will also help ensure that patient information leaflets do not produce unnecessary ‘nocebo’ effects.

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