Nocebo effects and participant information leaflets: evaluating information provided on adverse effects in UK clinical trials

Abstract

Background: Nocebo effects ('negative placebo' effects) experienced by clinical trial participants can arise from an underlying condition or through communication about side effects in the participant information leaflets (or elsewhere). Misattributing nocebo effects to the medicinal intervention can lead to participants experiencing harmful nocebo effects and may result in distortion of adverse effect reporting. However, little is known about how information on potential side effects is provided to trial participants. There is increasing concern that the way in which potential side effects in clinical trials are described to patients in participant information leaflets (PIL) can in itself cause harm by either increased anxiety, poor adherence or inducing the side effect itself. In this study, we aimed to explore these concerns and identify the way in which potential side effects from investigational medicinal products used in trials are presented in written information to potential participants. Methods: Trials were identified from the International Standard Randomised Controlled Trials Number (ISRCTN) clinical trial registry (a primary registry of the WHO International Clinical Trials Registry Platform (ICTRP)). Eligible studies were placebo-controlled clinical trials of investigational medicinal products (IMP) in adults conducted in the UK. We assessed readability using the Flesch Reading Ease scale, Gunning-Fog Index and Flesch-Kincaid Grade. Data extracted from the PILs were divided into 8 predefined qualitative themes for analysis in NVivo11. Results: Most of the patient information leaflets were ranked as 'fairly difficult to read' or 'difficult to read' according to the Flesch Reading Ease scale. All studies presented information about adverse events, whereas only a third presented information about intervention benefits. Where intervention or study benefits were presented, they were usually after adverse events (21/33, 64%). Discussion: Participant information leaflets scored poorly on ease of readability and had more content relating to adverse effects than any potential beneficial effects. The way in which adverse events were presented was heterogeneous in terms of their likelihood and severity and the amount and level of detail provided. By comparison, potential benefits from the intervention and/or study were described less often, by shorter text, and only after information about harms.

Creating concise and readable patient information sheets for interventional studies in Australia: are we there yet?

“…Conversely, Australian templates are criticised for their rigidity and focus on mitigating the risk of medico-legal exposure [ 35 ]. Some commentators suggest an excessive focus on risk can harm study participants through a phenomenon known as ‘the nocebo effect’ [ 36 ], when excessive risk information results in participants expecting side effects and thus experiencing side effects. Others suggest that legalistic PICFs can lead to the inappropriate rejection of studies due to an exaggerated perception of risk [ 37 , 38 ].…”

Developing principles for sharing information about potential trial intervention benefits and harms with patients: report of a modified Delphi survey

“…We generated a list of potential information about benefits and harms from three sources that background research suggested to be important: Principles and examples from our review of UK PILs [ 1 ] Extracted principles and examples from a random sample of Drug Facts Boxes [ 8 ] Statements from official guidance about presenting trial benefits and harms in PILs from within the UK (e.g. Health Research Authority (HRA) [ 9 ]) and internationally (e.g.…”

“…The potential benefits and risks of trial interventions are not communicated to patients in a consistent way. In a recent analysis of 33 participant information leaflets (PILs) used in trials conducted by the National Institute of Health Research (NIHR) in the UK [ 1 ], the way information about potential harms was communicated was found to be inconsistent. Most of the leaflets contained more information about harms than potential benefits, and some did not mention potential benefits at all.…”

Four reasons why too many informed consents to clinical research are invalid: a critical analysis of current practices

“…However, explanations on expected benefits usually do not exceed more than 12 lines. Kirby et al 21 reported that only one-third of the assessed IC documents mentioned specific potential benefits such as an expected delay of cancer progression; in these cases, information on benefits were usually found after description of adverse effects and presented by relatively shorter text. Along similar lines, the aforementioned study within a neuro-oncological research centre found that none of the analysed IC documents allowed a profound risk–benefit assessment.…”

“…Moreover, framing the likelihood of adverse effects negatively (eg, 10% will experience fatigue vs positively framed, eg, 90% will not experience fatigue) can even affect participant well-being as it may contribute to increased fears and negative expectations that itself cause adverse effects in the sense of a nocebo effect. 21 23 …”