{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:32:37Z","timestamp":1790555557021,"version":"4.1.0"},"reference-count":47,"publisher":"National Institute for Health and Care Research","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000664","name":"Health Technology Assessment programme","doi-asserted-by":"publisher","award":["MR\/V020706\/1"],"award-info":[{"award-number":["MR\/V020706\/1"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journalslibrary.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["Health Technol Assess"],"abstract":"<jats:sec id=\"abs1-1\"><jats:title>Background<\/jats:title>\n<jats:p>Variation in the way information about potential trial intervention benefits and harms is conveyed within patient information leaflets can cause avoidable information-induced (\u2018nocebo\u2019) harm, research waste, and may be unethical.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-2\"><jats:title>Objectives<\/jats:title>\n<jats:list list-type=\"order\">\n<jats:list-item><jats:p>To develop stakeholder-informed principles to guide how to describe information about potential trial intervention benefits and harms within patient information leaflets.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>To test whether using these principles are feasible for testing in trials that measure whether they improve recruitment and adverse event rates.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>To develop and disseminate guidance on how to implement the principles.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:sec>\n<jats:sec id=\"abs1-3\"><jats:title>Methods<\/jats:title>\n<jats:p>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 \u2018principled patient information leaflets\u2019. 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.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-4\"><jats:title>Results<\/jats:title>\n<jats:p>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 \u2018serious\u2019 and \u2018less serious\u2019, (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,\u00a0and (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.<\/jats:p>\n<jats:p>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.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-5\"><jats:title>Conclusions<\/jats:title>\n<jats:p>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.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-6\"><jats:title>Limitations:<\/jats:title>\n<jats:p>Due to\u00a0COVID-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\u00a0this 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.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-7\"><jats:title>Future work<\/jats:title>\n<jats:p>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.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-8\"><jats:title>Funding<\/jats:title>\n<jats:p>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 <jats:italic>Health Technology Assessment<\/jats:italic>; Vol. 29, No. 43.<\/jats:p>\n<\/jats:sec>","DOI":"10.3310\/gjjh2402","type":"journal-article","created":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T09:27:22Z","timestamp":1755941242000},"page":"1-20","update-policy":"https:\/\/doi.org\/10.3310\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Developing evidence-based guidelines for describing potential benefits and harms within patient information leaflets\/sheets (PILs) that inform and do not cause harm (PrinciPILs)"],"prefix":"10.3310","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0280-7206","authenticated-orcid":true,"given":"Jeremy","family":"Howick","sequence":"first","affiliation":[{"name":"Centre for Trials Research, Cardiff University, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7949-4039","authenticated-orcid":true,"given":"Martina","family":"Svobodova","sequence":"additional","affiliation":[{"name":"Centre for Trials Research, Cardiff University, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7239-7241","authenticated-orcid":true,"given":"Shaun","family":"Treweek","sequence":"additional","affiliation":[{"name":"Aberdeen Centre for Evaluation, University of Aberdeen, Aberdeen, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7890-2854","authenticated-orcid":true,"given":"Katie","family":"Gillies","sequence":"additional","affiliation":[{"name":"Aberdeen Centre for Evaluation, University of Aberdeen, Aberdeen, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6228-4446","authenticated-orcid":true,"given":"Adrian","family":"Edwards","sequence":"additional","affiliation":[{"name":"Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9558-3349","authenticated-orcid":true,"given":"Peter","family":"Bower","sequence":"additional","affiliation":[{"name":"Division of Population Health, Health Services Research & Primary Care, University of Manchester, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9261-9350","authenticated-orcid":true,"given":"Jennifer","family":"Bostock","sequence":"additional","affiliation":[{"name":"Centre for Trials Research, Cardiff University, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3240-4179","authenticated-orcid":true,"given":"Nina","family":"Jacob","sequence":"additional","affiliation":[{"name":"Centre for Trials Research, Cardiff University, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5268-8631","authenticated-orcid":true,"given":"Kerenza","family":"Hood","sequence":"additional","affiliation":[{"name":"Centre for Trials Research, Cardiff University, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"6221","published-online":{"date-parts":[[2025,8]]},"reference":[{"key":"key2025082314241800_ref1-bib1","volume-title":"Developing and Testing Participant Information Leaflets (PILs) That Inform and Do Not Cause Harm (PrinciPILs)","author":"UK Research and Innovation"},{"key":"key2025082314241800_ref2-bib2","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1186\/s13063-020-04591-w","article-title":"Nocebo effects and participant information leaflets: evaluating information provided on adverse effects in UK clinical trials","volume":"21","author":"Kirby","year":"2020","journal-title":"Trials"},{"key":"key2025082314241800_ref3-bib3","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1186\/s13063-024-08087-9","article-title":"When describing harms and benefits to potential trial participants, participant information leaflets are inadequate","volume":"25","author":"Cuddihy","year":"2024","journal-title":"Trials"},{"key":"key2025082314241800_ref4-bib4","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1136\/medethics-2019-105903","article-title":"Unethical informed consent caused by overlooking poorly measured nocebo effects","volume":"47","author":"Howick","year":"2020","journal-title":"J Med Ethics"},{"key":"key2025082314241800_ref5-bib5","volume-title":"The Medicines for Human Use (Clinical Trials) Regulations 2004","author":"Legislation.gov.uk"},{"key":"key2025082314241800_ref6-bib6","volume-title":"2018 Requirements (2018 Common Rule)","author":"Office for Human Research Protections"},{"key":"key2025082314241800_ref7-bib7","volume-title":"Regulation (EU) No 536\/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001\/20\/EC Text with EEA relevance","author":"EUR-Lex"},{"key":"key2025082314241800_ref8-bib8","volume-title":"The Declaration of Helsinki","author":"World Medical Association"},{"key":"key2025082314241800_ref9-bib9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1749-799X-5-1","article-title":"Effects of low power laser irradiation on bone healing in animals: a meta-analysis","volume":"5","author":"Bashardoust Tajali","year":"2010","journal-title":"J Orthop Surg Res"},{"key":"key2025082314241800_ref10-bib10","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.conctc.2018.08.001","article-title":"Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: a review","volume":"11","author":"Fogel","year":"2018","journal-title":"Contemp Clin Trials Commun"},{"key":"key2025082314241800_ref11-bib11","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1186\/s13063-019-3704-x","article-title":"Reducing research waste by promoting informed responses to invitations to participate in clinical trials","volume":"20","author":"Gillies","year":"2019","journal-title":"Trials"},{"key":"key2025082314241800_ref12-bib12","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1186\/s13063-018-3042-4","article-title":"Rapid overview of systematic reviews of nocebo effects reported by patients taking placebos in clinical trials","volume":"19","author":"Howick","year":"2018","journal-title":"Trials"},{"key":"key2025082314241800_ref13-bib13","doi-asserted-by":"crossref","first-page":"532","DOI":"10.7326\/0003-4819-153-8-201010190-00010","article-title":"What\u2019s in placebos: who knows? Analysis of randomized, controlled trials. Research Support, Non-U.S. Gov\u2019t","volume":"153","author":"Golomb","year":"2010","journal-title":"Ann Intern Med"},{"key":"key2025082314241800_ref14-bib14","doi-asserted-by":"crossref","first-page":"e13169","DOI":"10.1111\/eci.13169","article-title":"Inadequate description of placebo and sham controls in a systematic review of recent trials","volume":"49","author":"Webster","year":"2019","journal-title":"Eur J Clin Invest"},{"key":"key2025082314241800_ref15-bib15","first-page":"e100329","article-title":"TIDieR-Placebo: a guide and checklist for reporting placebo and sham controls","volume":"7","author":"Howick","year":"2020","journal-title":"PLOS Med"},{"key":"key2025082314241800_ref16-bib16","doi-asserted-by":"crossref","first-page":"186","DOI":"10.2471\/BLT.14.141390","article-title":"Participants\u2019 understanding of informed consent in clinical trials over three decades: systematic review and meta-analysis","volume":"93","author":"Tam","year":"2015","journal-title":"Bull World Health Organ"},{"key":"key2025082314241800_ref17-bib17","article-title":"Open Science Framework","author":"Svobodova","year":"2021","journal-title":"Developing Core Principles for Sharing Information about Potential Intervention Benefits and Harms in Patient Information Leaflets Using a Modified Delphi Survey"},{"key":"key2025082314241800_ref18-bib18","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3310\/nihropenres.13420.1","article-title":"Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets","volume":"3","author":"Howick","year":"2023","journal-title":"NIHR Open Res"},{"key":"key2025082314241800_ref19-bib19","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1186\/s13063-022-06780-1","article-title":"Developing principles for sharing information about potential trial intervention benefits and harms with patients: report of a modified Delphi survey","volume":"23","author":"Svobodova","year":"2022","journal-title":"Trials"},{"key":"key2025082314241800_ref20-bib20","doi-asserted-by":"crossref","first-page":"516","DOI":"10.7326\/0003-4819-150-8-200904210-00106","article-title":"Using a drug facts box to communicate drug benefits and harms: two randomized trials","volume":"150","author":"Schwartz","year":"2009","journal-title":"Ann Intern Med"},{"key":"key2025082314241800_ref21-bib21","volume-title":"Content: Participant Information Sheet \u2013 What\u2019s Involved","author":"Health Research Authority"},{"key":"key2025082314241800_ref22-bib22","volume-title":"ICH E6 (R2) Good Clinical Practice","author":"European Medicines Agency"},{"key":"key2025082314241800_ref23-bib23","volume-title":"Research Ethics Review Committee (ERC): Templates for Informed Consent Forms","author":"World Health Organisation"},{"key":"key2025082314241800_ref25-bib25","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.jclinepi.2013.12.002","article-title":"Defining consensus: a systematic review recommends methodologic criteria for reporting of Delphi studies","volume":"67","author":"Diamond","year":"2014","journal-title":"J Clin Epidemiol"},{"key":"key2025082314241800_ref26-bib26","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3310\/nihropenres.13423.1","article-title":"Co-production of guidance and resources to implement principled participant information leaflets (PrinciPILs)","volume":"3","author":"Jacob","year":"2023","journal-title":"NIHR Open Res"},{"key":"key2025082314241800_ref27-bib27","volume-title":"ATLANTIS: AnTiconvuLsant AugmeNtation Trial In Schizophrenia","author":"National Institute for Health Research"},{"key":"key2025082314241800_ref28-bib28","volume-title":"ALABAMA Study: ALlergy AntiBiotics And Microbial Resistance","author":"Department of Primary Care Health Sciences UoO"},{"key":"key2025082314241800_ref29-bib29","volume-title":"VELRAD: Video Endoscopic Inguinal Lymphadectomy versus RADical Open Dissection","author":"National Institute for Health Research"},{"key":"key2025082314241800_ref31-bib31","volume-title":"The PICCOS Trial (PIPAC in Cancers of the Colon, Ovaries and Stomach): A Randomised Controlled Phase II Trial in Colorectal, Ovarian and Stomach Cancers to Define the Efficacy of Pressurised IntraPeritoneal Aerosolised Chemotherapy (PIPAC) in the Management of Peritoneal Metastases","author":"Centre for Trials Research"},{"key":"key2025082314241800_ref32-bib32","article-title":"Implementing consensus-based principles to transform patient information leaflets into \u2018principled patient information leaflets\u2019 (PrinciPILs)","author":"Howick","year":"2023","journal-title":"osfio"},{"key":"key2025082314241800_ref33-bib33","volume-title":"SWAT 161: \u2018Principled\u2019 versus Usual Approach for Sharing Information about Potential Benefits and Harms of Trial Interventions in Patient Information Leaflets","author":"MRC Hubs for Trials Methodology Research"},{"key":"key2025082314241800_ref34-bib34","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s13063-025-08824-8","article-title":"Variation in the extent to which patient information leaflets describe potential benefits and harms of trial interventions: a commentary","volume":"26","author":"Howick","year":"2025","journal-title":"Trials"},{"key":"key2025082314241800_ref36-bib36","volume-title":"pils","author":"Howick"},{"key":"key2025082314241800_ref37-bib37","doi-asserted-by":"crossref","first-page":"e0242239","DOI":"10.1371\/journal.pone.0242239","article-title":"A systematic review of risk communication in clinical trials: how does it influence decisions to participate and what are the best methods to improve understanding in a trial context?","volume":"15","author":"Coyle","year":"2020","journal-title":"PLOS ONE"},{"key":"key2025082314241800_ref38-bib38","volume-title":"PrinciPIL Guidance for Research Ethics Committees and Researchers","author":"Howick","year":"2022"},{"key":"key2025082314241800_ref39-bib39","author":"Centre for Trials Research"},{"key":"key2025082314241800_ref40-bib40","volume-title":"PrinciPIL","author":"Howick"},{"key":"key2025082314241800_ref41-bib41","volume-title":"CLAXON: @The_MRC PrinciPIL SUCCESSFULLY COMPLETE! X","author":"Howick"},{"key":"key2025082314241800_ref42-bib42","doi-asserted-by":"crossref","first-page":"E2","DOI":"10.1186\/1472-6939-3-2","article-title":"International variation in ethics committee requirements: comparisons across five Westernised nations","volume":"3","author":"Goodyear-Smith","year":"2002","journal-title":"BMC Med Ethics"},{"key":"key2025082314241800_ref44-bib44","doi-asserted-by":"crossref","first-page":"23814683211042832","DOI":"10.1177\/23814683211042832","article-title":"Educating pharmacists on the risks of strong opioids with descriptive and simulated experience risk formats: a randomized controlled trial","volume":"6","author":"Wegwarth","year":"2021","journal-title":"MDM Policy Pract"},{"key":"key2025082314241800_ref45-bib45","first-page":"MR000013","article-title":"Strategies to improve recruitment to randomised trials","volume":"2","author":"Treweek","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"key":"key2025082314241800_ref46-bib46","first-page":"MR000032","article-title":"Strategies to improve retention in randomised trials","volume":"3","author":"Gillies","year":"2021","journal-title":"Cochrane Database Syst Rev"},{"key":"key2025082314241800_ref47-bib47","doi-asserted-by":"crossref","first-page":"e0268898","DOI":"10.1371\/journal.pone.0268898","article-title":"Information about dissemination of trial results in patient information leaflets for clinicals trials in the UK and Ireland: the what and the when","volume":"17","author":"Bjorklund","year":"2022","journal-title":"PLOS ONE"},{"key":"key2025082314241800_ref48-bib48","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.jclinepi.2016.07.016","article-title":"A systematic review of discontinued trials suggested that most reasons for recruitment failure were preventable","volume":"80","author":"Briel","year":"2016","journal-title":"J Clin Epidemiol"},{"key":"key2025082314241800_ref49-bib49","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s12961-022-00838-x","article-title":"Co-production practice and future research priorities in United Kingdom-funded applied health research: a scoping review","volume":"20","author":"Smith","year":"2022","journal-title":"Health Res Policy Syst"},{"key":"key2025082314241800_ref50-bib50","volume-title":"Unnecessary Harm Caused by Informed Consent.","author":"Howick","year":"2021"},{"key":"key2025082314241800_ref51-bib51","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1136\/bmj.p1233","article-title":"On the ethical requirement to inform patients about potential treatment benefits","volume":"381","author":"Howick","year":"2023","journal-title":"BMJ"}],"container-title":["Health Technology Assessment"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/njl-admin.nihr.ac.uk\/document\/download\/2048700","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.journalslibrary.nihr.ac.uk\/sites\/journalslibrary\/files\/journal_data\/GJJH2402\/GJJH2402.xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/njl-admin.nihr.ac.uk\/document\/download\/2048700","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T09:27:32Z","timestamp":1755941252000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.journalslibrary.nihr.ac.uk\/hta\/GJJH2402"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":47,"alternative-id":["10.3310\/GJJH2402"],"URL":"https:\/\/doi.org\/10.3310\/gjjh2402","relation":{},"ISSN":["2046-4924"],"issn-type":[{"value":"2046-4924","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8]]},"assertion":[{"value":"This content has been made freely available to all.","name":"free","label":"Free to read"},{"value":"10-2020","name":"contractual_start_date","label":"contractual_start_date","group":{"name":"article_history","label":"Article History"}},{"value":"10-2023","name":"editorial_review_begun","label":"editorial review begun","group":{"name":"article_history","label":"Article History"}},{"value":"04-2025","name":"accepted_for_publication","label":"Accepted for publication","group":{"name":"article_history","label":"Article History"}}]}}