Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis

Keywords Communication, harms, nocebo, placebo, research ethics, meta-analysis, harms, adverse events, recruitment ALL Metrics - Views Downloads How to cite this article Howick J, Svobodova M, Treweek S et al. Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis [version 1; peer review: 2 approved, 2 approved with reservations]. NIHR Open Res 2023, 3:29 (https://doi.org/10.3310/nihropenres.13420.1) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente Select a format first ▬ ✚ Study Protocol [version 1; peer review: 2 approved, 2 approved with reservations] Jeremy Howick https://orcid.org/0000-0003-0280-7206 1, Martina Svobodova https://orcid.org/0000-0001-7949-4039 1, Shaun Treweek2, [...] Nina Jacob1, Katie Gillies2, Jennifer Bostock1, Peter Bower3, Adrian Edwards4, K Hood1Jeremy Howick https://orcid.org/0000-0003-0280-7206 1, Martina Svobodova https://orcid.org/0000-0001-7949-4039 1, [...] Shaun Treweek2, Nina Jacob1, Katie Gillies2, Jennifer Bostock1, Peter Bower3, Adrian Edwards4, K Hood1 PUBLISHED 26 May 2023 Author details Author details 1 Centre for Trials Research (CTR), College of Biomedical and Life Sciences, Cardiff University, Cardiff, Wales, UK 2 Health Services Research Unit, University of Aberdeen, Aberdeen, Scotland, UK 3 Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, England, UK 4 Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, Wales, UK 2 Health Services Research Unit, University of Aberdeen, Aberdeen, Scotland, UK 3 Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, England, UK 4 Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, Wales, UK Jeremy Howick Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Martina Svobodova Roles: Conceptualization, Methodology, Project Administration, Writing – Review & Editing Roles: Conceptualization, Methodology, Project Administration, Writing – Review & Editing Shaun Treweek Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Nina Jacob Roles: Conceptualization, Methodology, Writing – Review & Editing Roles: Conceptualization, Methodology, Writing – Review & Editing Katie Gillies Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Jennifer Bostock Roles: Conceptualization, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Peter Bower Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Adrian Edwards Roles: Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing K Hood Roles: Conceptualization, Formal Analysis, Funding Acquisition, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Formal Analysis, Funding Acquisition, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW REVIEWER STATUS The way potential benefits and harms of trial interventions are shared within patient information leaflets (PILs) varies widely and may cause unnecessary harms (“nocebo effects”). The aim of this meta-analysis will be to evaluate the influence on recruitment rates and early effects on patient reported adverse events of principled patient information leaflets (PrinciPILs) compared with standard PILs. Eligible studies will include those that report the effects on recruitment and patient reported adverse events of PrinciPILs compared to standard PILs. We will include in this meta-analysis all the standard PILs in studies within trials (SWATs) of PrinciPILs that were developed as part of the Medical Research Council (MRC) funded PrinciPIL project. By publishing this as a living meta-analysis, we will allow the meta-analysis to be updated with future SWATs of PrinciPILs. We will use the Cochrane Risk of Bias tool to evaluate the risk of bias for each outcome. We will report the total number of studies and participants analysed and the characteristics of included studies (including details of intervention, comparators, outcomes). For dichotomous data, we will calculate the risk difference and the risk ratio (RR) and 95% confidence intervals (CIs). For continuous outcomes we will use weighted mean differences with 95% CIs or standardized mean differences with 95% CIs. We will investigate heterogeneity by visually inspecting the forest plot and by considering the I2 test result. We will assess the certainty warranted for each outcome using the Grading of Recommendations Assessment Development and Evaluation (GRADE). Ethics approval is not applicable since no original data will be collected. The results will be disseminated through peer-reviewed publication and conference presentations. We will discuss the limitations of the meta-analysis including study risk of bias, inconsistency, heterogeneity, and imprecision. A general interpretation of the results and important implications will be provided. People who take part in randomised trials need to understand the risks as well as the benefits of taking part. Most ‘patient information leaflets’ (PILs) that describe trial treatments include information about harms. Yet only some PILs contain information about potential benefits. This variation is confusing. Also, the over-emphasis on harms can cause “nocebo” effects, which are the harms caused by expecting something bad to happen. To solve these problems, we have developed seven principles that ensure that information about potential benefits and harms in PILs is balanced and consistent. We will now compare PILs that have been developed according to our principles (we call these ‘PrinciPILs’) with PILs that have not been developed with our principles. We will test whether PrinciPILs reduce nocebo effects and improve trial recruitment. Here we have described our plans to test the effect of PrinciPILs in a few trials. Communication, harms, nocebo, placebo, research ethics, meta-analysis, harms, adverse events, recruitment Corresponding Author(s) Jeremy Howick ([email protected]) Grant information: This project is funded by the National Institute for Health Research (NIHR) under its [‘Programme Grants for Applied Research Programme’ (Grant Reference Number RP-PG-1016-20010)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This meta-analysis is also funded by the Medical Research Council (MRA reference MR/V020706/1). Cardiff University is the sponsor for this research. Neither the funder nor the sponsor was involved in any other aspect of the project, such as the design of the project’s protocol and analysis plan, the collection and analyses. The funder will have no input on the interpretation or publication of the study results. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2023 Howick J et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Howick J, Svobodova M, Treweek S et al. Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis [version 1; peer review: 2 approved, 2 approved with reservations]. NIHR Open Res 2023, 3:29 (https://doi.org/10.3310/nihropenres.13420.1) First published: 26 May 2023, 3:29 (https://doi.org/10.3310/nihropenres.13420.1) Latest published: 26 May 2023, 3:29 (https://doi.org/10.3310/nihropenres.13420.1) RP-PG-1016-20010)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This meta-analysis is also funded by the Medical Research Council (MRA reference MR/V020706/1). Cardiff University is the sponsor for this research. Neither the funder nor the sponsor was involved in any other aspect of the project, such as the design of the project’s protocol and analysis plan, the collection and analyses. The funder will have no input on the interpretation or publication of the study results. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Recent research has identified several problems with the way in which information about potential benefits and harms of trial treatments are presented within patient information leaflets (PILs). A review of 33 PILs from trials registered with the International Standard Randomised Controlled Trials Number (ISRCTN) clinical trial registry found that the way in which this information is presented varies widely, with some PILs not mentioning potential benefits at all1. Relatedly, an overview of systematic reviews including over 250,000 trial participants given placebo treatments suggests that reported harms are increased by the way in which information about potential harms is presented2. Presenting potential benefits and harms in an unbalanced way can also adversely affect trial recruitment3. The way in which potential trial treatment benefits and harms are currently presented within PILs also raises a number of under-explored ethical issues. Specifically, emphasizing the need to share information about harms is needed for patients to provide informed consent, thus respecting the principle of autonomy. However, if the way in which this information is shared causes avoidable harm, this violates the ethical principle of non-maleficence (to do no harm)4. Meanwhile, current Health Research Authority (HRA) guidance on describing potential benefits and harms is brief and does not appear to be applied consistently1. The Medical Research Council (MRC) in the UK funded a project to help solve the problem with variation in way in which information about potential benefits of trial interventions is shared within PILs, and avoidable harm caused by this variation5,6. As part of the project, a range of stakeholders (including patient representatives, medico-legal experts, and trial researchers) developed principles that could be used to present information about potential benefits and harms within PILs in a more consistent way. The principles have been used to adapt PILs from five host clinical trials (‘standard PILs’). We call the adapted PILs ‘Principled Patient Information Leaflets (PrinciPILs)’. Having the principles can reduce variability and provide guidance to help those who design PILs (and ethics committees who evaluate them). In addition to being intrinsically valuable for reducing variability and harmonising the way PILs present information about potential benefits and harms of trial interventions, PrinciPILs are hypothesized to improve recruitment rates, reduce some reported harms, and improve quality of life4. To test this hypothesis, the PrinciPILs will be compared with standard PILs in studies within trials (SWATs). However, individual SWATs will not be powered to detect changes in recruitment rates or early outcomes. Also, single SWATs do not enable comparison and generalisability of results of SWATs across different types of trials, populations, protocols, processes, and outcomes7. This protocol was reported following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines8. The meta-analysis will be conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines9. A patient and public involvement (PPI) representative (JB) was involved in acquiring the funding for this study, question development, research design, and background research. The same PPI representative is involved in our ongoing active dissemination plan for this study. A meta-analysis of a small number of SWATs may demonstrate a difference in the main outcomes. However, additional SWATs are likely to be required for the pooled comparison to be adequately powered. In addition, the effect of PrinciPILs in different contexts, diseases populations, and outcomes is likely to vary10. Future SWATs of PrinciPILs are therefore likely to add relevant information about the effects of PrinciPILs. This meta-analysis is therefore designed to facilitate the inclusion of future SWATs of PrinciPILs. Any SWAT comparing PrinciPILs with standard PILs is eligible for this meta-analysis11. Population. We will not restrict the SWATs by population, and the trial populations of the SWATs varied widely. Intervention. The intervention for the included trials will be PrinciPILs. Comparators. The comparators for the studies will be standard PILs. These will be the PILs produced by the research teams of the host trials. We will summarize the differences between the PrinciPILs and standard PILs in a table. Outcomes. As agreed with the host trials, we will collect data on recruitment rates and early outcomes (within 3 months). We collected any early outcome that the host trial collected, and we anticipate that these will include data related to quality of life, pain, patient satisfaction, and retention. Timing. At recruitment and up to 3 months post-recruitment. Setting. There will be no restrictions by type of setting. Language. We anticipate that all trials will be reported in English, however, we will not place a language restriction on the PILs. We will include all the SWATs of PrinciPILs that were developed as part of the MRC funded PrinciPIL project (as yet to be determined) in this meta-analysis. By publishing our study as a living meta-analysis, it may also be updated with future SWATs of PrinciPILs. We have included the protocol for SWATs of PrinciPILs on the Northern Ireland Trials Methodology Repository so that future researchers can conduct SWATs of PrinciPILs11. Data collection process. Using standardized pre-piloted forms (Microsoft Excel) and an instruction manual, two reviewers will input data independently with discrepancies resolved in discussion with a third reviewer. We will contact host study authors to resolve any uncertainties. We will report the name of the experimental and control interventions, a full description of both the intervention and control interventions, (where available) patient characteristics (average age, gender, ethnicity, symptoms), trial design, trial size, duration of follow-up, type and source of financial support. We will report differences between the intervention (PrinciPIL) and control (standard PIL) groups. This will include differences in recruitment rates and all available early outcomes (gathered within 3 months of randomisation). We anticipate that these outcomes will include patient reported adverse events, quality of life, mortality, and trial recruitment rates. Since it can be difficult to distinguish between adverse events and illness symptoms, we will include patient reported illness symptoms as adverse events. We will use the Cochrane Risk of Bias tool (Rob2) to evaluate the risk of bias for each outcome. This tool includes five domains: bias arising from randomisation process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of outcome, bias in selection of the reported result. In addition, an additional domain is available for cluster randomised trials; bias arising from identification or recruitment of individual participants within clusters. The risk of bias will be related to the implementation of the SWAT. Two reviewers will independently assess the risk of bias, with discrepancies being resolved by discussion with a senior reviewer (JH) if necessary. We will calculate differences for all outcomes between the intervention and control. For dichotomous data, we will calculate the risk difference and the risk ratio (RR) and 95% confidence intervals (CIs). For continuous outcomes we will use weighted mean differences with 95% CIs or standardized mean differences with 95% CIs. We will start with a narrative synthesis of the results in the text and tables that summarizes the study characteristics and results. Because the interventions and control will be homogeneous by design, we anticipate being able to legitimately pool the results. We are also aware that the underlying populations differ and we will therefore use a random effects model. We will use Cochrane’s statistical software RevMan, and the statistical guidelines from the current version of the Cochrane Handbook will be followed12. Due to the heterogeneity of the included trials we will use the random effects model. Although the included studies will be chosen for homogeneity of intervention and control, we will assess heterogeneity to confirm whether pooling data is legitimate. We will adjust for clustering using intra-cluster coefficient estimates and average cluster sizes. Subgroup and sensitivity analyses. Evidence suggests that the effect of varying communication is likely to vary according to type of disease and type of outcome13,14. When the number of SWATs included in this meta-analysis permits, we will do separate analyses for different disease groups (for example, cancer, musculoskeletal, mental illness), population types (for example, children, adults), and intervention types (for example, psychological, pharmacological). To help determine whether there were meta-biases, we will investigate whether the outcomes in the meta-analysis were pre-specified in a protocol. We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method to determine the confidence in cumulative evidence. This will involve assessment across all GRADE domains (risk of bias, consistency, directness, precision, and publication bias). The outcome of the GRADE assessment will be an overall assessment of the confidence in cumulative evidence as high, moderate, low, or very low. In the event of protocol amendments, the date of each amendment will be accompanied by a description of the change and the rationale. This meta-analysis has not begun. The results will be disseminated through peer reviewed publication (a living meta-analysis) and conference presentations. Our systematic review protocol will be uploaded to ResearchGate. Ethics approval is not required for this study since no original data will be gathered. Consent for participation is not relevant as there are no participants. Harvard Dataverse: PRISMA-P checklist for ‘Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis’. https://doi.org/10.7910/DVN/2IQO1H8 Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). Faculty Opinions recommendedReferences - 1. Kirby N, Shepherd V, Howick J, et al.: Nocebo effects and participant information leaflets: evaluating information provided on adverse effects in UK clinical trials. Trials. 2020; 21(1): 658. PubMed Abstract | Publisher Full Text | Free Full Text - 2. Howick J, Webster R, Kirby N, et al.: Rapid overview of systematic reviews of nocebo effects reported by patients taking placebos in clinical trials. Trials. 2018; 19(1): 674. PubMed Abstract | Publisher Full Text | Free Full Text - 3. Treweek S, Pitkethly M, Cook J, et al.: Strategies to improve recruitment to randomised trials. Cochrane Database Syst Rev. 2018; 2: MR000013. PubMed Abstract | Publisher Full Text | Free Full Text - 4. Howick J: Unethical informed consent caused by overlooking poorly measured nocebo effects. J Med Ethics. 2021; 47(9): 590–594. PubMed Abstract | Publisher Full Text - 5. PrinciPILs. Reference Source - 6. Sovoboda M, Jacob N, Hood K, et al.: Developing principles for sharing information about potential trial intervention benefits and harms with patients: report of a modified Delphi survey. Trials. 2022; 23(1): 863. PubMed Abstract | Publisher Full Text | Free Full Text - 7. Peng J, Clarkin C, Doja A: Uncovering cynicism in medical training: A qualitative analysis of medical online discussion forums. BMJ Open. 2018; 8(10): e022883. PubMed Abstract | Publisher Full Text | Free Full Text - 8. Howick J: PRISMA-P Checklist for "Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis". Harvard Dataverse. V1. [Dataset]. 2023. http://www.doi.org/10.7910/DVN/2IQO1H - 9. Page MJ, Moher D, Bossuyt PM, et al.: PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021; 372: n160. PubMed Abstract | Publisher Full Text | Free Full Text - 10. Howick J, Friedemann C, Tsakok M, et al.: Are treatments more effective than placebos? A systematic review and meta-analysis. PLoS One. 2013; 8(5): e62599. PubMed Abstract | Publisher Full Text | Free Full Text - 11. The Northern Ireland Hub for Trials Methodology Research. Reference Source - 12. Higgins JJ, Green S: The Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011] edn. Chichester: The Cochrane Collaboration; 2011. Reference Source - 13. Howick J, Hoffmann T: How placebo characteristics can influence estimates of intervention effects in trials. CMAJ. 2018; 190(30): E908-E911. PubMed Abstract | Publisher Full Text | Free Full Text - 14. Kong J, Spaeth R, Cook A, et al.: Are all placebo effects equal? Placebo pills, sham acupuncture, cue conditioning and their association. PLoS One. 2013; 8(7): e67485. PubMed Abstract | Publisher Full Text | Free Full Text Author details Author details 1 Centre for Trials Research (CTR), College of Biomedical and Life Sciences, Cardiff University, Cardiff, Wales, UK 2 Health Services Research Unit, University of Aberdeen, Aberdeen, Scotland, UK 3 Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, England, UK 4 Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, Wales, UK 2 Health Services Research Unit, University of Aberdeen, Aberdeen, Scotland, UK 3 Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, England, UK 4 Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, Wales, UK Jeremy Howick Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Martina Svobodova Roles: Conceptualization, Methodology, Project Administration, Writing – Review & Editing Roles: Conceptualization, Methodology, Project Administration, Writing – Review & Editing Shaun Treweek Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Nina Jacob Roles: Conceptualization, Methodology, Writing – Review & Editing Roles: Conceptualization, Methodology, Writing – Review & Editing Katie Gillies Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Jennifer Bostock Roles: Conceptualization, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Peter Bower Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Adrian Edwards Roles: Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing K Hood Roles: Conceptualization, Formal Analysis, Funding Acquisition, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Formal Analysis, Funding Acquisition, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This project is funded by the National Institute for Health Research (NIHR) under its [‘Programme Grants for Applied Research Programme’ (Grant Reference Number RP-PG-1016-20010)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This meta-analysis is also funded by the Medical Research Council (MRA reference MR/V020706/1). Cardiff University is the sponsor for this research. Neither the funder nor the sponsor was involved in any other aspect of the project, such as the design of the project’s protocol and analysis plan, the collection and analyses. The funder will have no input on the interpretation or publication of the study results. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. RP-PG-1016-20010)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This meta-analysis is also funded by the Medical Research Council (MRA reference MR/V020706/1). Cardiff University is the sponsor for this research. Neither the funder nor the sponsor was involved in any other aspect of the project, such as the design of the project’s protocol and analysis plan, the collection and analyses. The funder will have no input on the interpretation or publication of the study results. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright © 2023 Howick J et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. metrics VIEWS $counts.viewCount downloads Citations CITE how to cite this article Howick J, Svobodova M, Treweek S et al. Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis [version 1; peer review: 2 approved, 2 approved with reservations]. NIHR Open Res 2023, 3:29 (https://doi.org/10.3310/nihropenres.13420.1) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. track receive updates on this article Track an article to receive email alerts on any updates to this article. Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 26 May 2023 Views 0 How to cite this report: Kang J. Reviewer Report For: Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis [version 1; peer review: 2 approved, 2 approved with reservations]. NIHR Open Res 2023, 3:29 (https://doi.org/10.3310/nihropenres.14554.r31354) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-31354 https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-31354 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 16 May 2024 Approved VIEWS 0 This study protocol aims to assess the effects of recruitment rates and patient reported outcomes (including adverse outcomes) by comparing ‘principled patient information leaflet’ versus ‘standard patient information leaflet’. The rationale and background are clearly described, and the study ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close The rationale and background are clearly described, and the study ... Continue reading This study protocol aims to assess the effects of recruitment rates and patient reported outcomes (including adverse outcomes) by comparing ‘principled patient information leaflet’ versus ‘standard patient information leaflet’. The rationale and background are clearly described, and the study design is appropriate for the research question. Overall, I feel this protocol is well designed and considered all possible biases and heterogeneity, and proposed solutions or assessments on those. The research idea is clinical meaningful and have good patient benefit implications. However, I have some major concerns: The rationale and background are clearly described, and the study design is appropriate for the research question. Overall, I feel this protocol is well designed and considered all possible biases and heterogeneity, and proposed solutions or assessments on those. The research idea is clinical meaningful and have good patient benefit implications. However, I have some major concerns: - The inclusion criteria are very board: no restriction of disease type, population, intervention methods, etc. Especially for the disease type, it wouldn’t be fair to pool all disease types and compare their recruitment rate, as rare disease and common disease are hardly comparable regardless of the outcome measures. - If the included number of trials are too large, how can the research team ensure completion of the project within the required timeframe? - Is the rationale for, and objectives of, the study clearly described? Yes - Is the study design appropriate for the research question? Yes - Are sufficient details of the methods provided to allow replication by others? Yes - Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: medical statistics CITE HOW TO CITE THIS REPORT Kang J. Reviewer Report For: Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis [version 1; peer review: 2 approved, 2 approved with reservations]. NIHR Open Res 2023, 3:29 (https://doi.org/10.3310/nihropenres.14554.r31354) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-31354 https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-31354 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Views 0 How to cite this report: Bruce J. Reviewer Report For: Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis [version 1; peer review: 2 approved, 2 approved with reservations]. NIHR Open Res 2023, 3:29 (https://doi.org/10.3310/nihropenres.14554.r31359) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-31359 https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-31359 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 01 Apr 2024 Approved with Reservations VIEWS 0 This is a well written protocol from a leading team of trial methodologists. The systematic review aims to evaluate whether adapted patient information leaflets increase participant recruitment to clinical trials, reduce harms and improve quality of life compared to 'standard' ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close This is a well written protocol from a leading team of trial methodologists. The systematic review aims to evaluate whether adapted patient information leaflets increase participant recruitment to clinical trials, reduce harms and improve quality of life compared to 'standard' PILS. A few points for the team to consider:- Just some things to consider, but overall a really interesting project and good luck to the research team. A few points for the team to consider:- - It would be helpful to add some more background detail on the principles and adaptations made in the five host trials. Were the same team involved with adapting the PILs for all host trials thus there is confidence that all adapted PILs are indeed fully 'adapted' and whether/how this will be monitored when future studies are added. If this protocol will be stand alone for future SWATS to be added, what judgements will be made at screening stage. Whether all of the principles need to be adhered to to fulfil the definition of PrinciPIL. - If you could check for consistency in relation to the description of outcomes across the protocol. The title states patient reported outcomes rather than patient-reported adverse events whereas the abstract states early effects on patient reported AEs. Under 'outcomes & prioritization' it specifies AEs, quality of life and mortality. Is the assumption here that the adapted PIL can reduce (or increase?) mortality? Also includes illness symptoms - but this could be any potential physical or psychological symptom thus the list could be very long. Whether to focus on symptoms with a potential mechanism of action e.g. anxiety, depression, catastrophizing etc. You do specify under subgroup analyses about disease groups but whether some classification is required for the illness symptoms/AEs. Are you only interested in patient-reported AE rather than site reported AEs- is there any consideration of expectedness? Or are all symptoms considered to be AEs. Will site-reported events be included? - Pain, patient satisfaction and retention are also mentioned under the eligibility criteria section. Thus the terminology or listing of outcomes needs to be consistent across the protocol. Whether to broadly categorise as i) process-related (or whatever terminology) for recruitment and retention issues, ii) patient-reported for specific symptoms, patient satisfaction etc. - Suggest add systematic review to title as may want to include future studies although they may not all contribute to the meta-analyses? Meta-analysis is the statistical technique for synthesis not study design (think is a PRISMA requirement). - If this is going to be a live ongoing review, will searches of bibliographic databases be conducted? Whether to add in a covering statement for future updates - obviously for this review you are starting with the five host trials but whether searches will be completed for updates. Thus just thinking about future-proofing your review protocol. Also assume any phase of trial would be eligible although assume all will probably be Phase III studies of healthcare interventions. Just some things to consider, but overall a really interesting project and good luck to the research team. - Is the rationale for, and objectives of, the study clearly described? Yes - Is the study design appropriate for the research question? Yes - Are sufficient details of the methods provided to allow replication by others? Partly - Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Clinical trials, rehabilitation research CITE HOW TO CITE THIS REPORT Bruce J. Reviewer Report For: Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis [version 1; peer review: 2 approved, 2 approved with reservations]. NIHR Open Res 2023, 3:29 (https://doi.org/10.3310/nihropenres.14554.r31359) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-31359 https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-31359 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Views 0 How to cite this report: Falahee M. Reviewer Report For: Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis [version 1; peer review: 2 approved, 2 approved with reservations]. NIHR Open Res 2023, 3:29 (https://doi.org/10.3310/nihropenres.14554.r31360) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-31360 https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-31360 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 29 Mar 2024 Approved with Reservations VIEWS 0 This protocol describes a living meta-analysis of studies within trials (SWATs) comparing standard patient information leaflets with versions that present information about benefits and harms in line with the principles developed in an MRC funded initiative to reduce variation in ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close This protocol describes a living meta-analysis of studies within trials (SWATs) comparing standard patient information leaflets with versions that present information about benefits and harms in line with the principles developed in an MRC funded initiative to reduce variation in the presentation of such information to trial participants (PrinciPILs). The protocol is well-written, the methods outlined are appropriate to address the research objectives with evidence of patient and public involvement, and the approach described follows appropriate guidelines. My comments are minor, and largely concern the provision of additional detail. 1. The introduction is very concise, and would benefit from more detailed exposition of the principles underlying the PrinciPILs, and how this differs from the standard approach. 2. The authors plan to summarize the differences between the PILs and the PrinciPILs for each trial. Please clarify whether/how inter-trial variation in the extent of the difference between the intervention and the comparator will be addressed in the analysis. 3. The authors note that future SWATs of PrinciPILs may be included in this living analysis. I assume this could possibly include SWATs undertaken by other research teams outside of the current project. If so please note how these will be identified. 4. Have the authors considered undertaking qualitative evaluation to explore participant responses to PILs and PrinciPILs? Could such information be incorporated into this study? If so, how? The protocol is well-written, the methods outlined are appropriate to address the research objectives with evidence of patient and public involvement, and the approach described follows appropriate guidelines. My comments are minor, and largely concern the provision of additional detail. 1. The introduction is very concise, and would benefit from more detailed exposition of the principles underlying the PrinciPILs, and how this differs from the standard approach. 2. The authors plan to summarize the differences between the PILs and the PrinciPILs for each trial. Please clarify whether/how inter-trial variation in the extent of the difference between the intervention and the comparator will be addressed in the analysis. 3. The authors note that future SWATs of PrinciPILs may be included in this living analysis. I assume this could possibly include SWATs undertaken by other research teams outside of the current project. If so please note how these will be identified. 4. Have the authors considered undertaking qualitative evaluation to explore participant responses to PILs and PrinciPILs? Could such information be incorporated into this study? If so, how? - Is the rationale for, and objectives of, the study clearly described? Yes - Is the study design appropriate for the research question? Yes - Are sufficient details of the methods provided to allow replication by others? Yes - Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: health psychology, patient preferences, mixed methods CITE HOW TO CITE THIS REPORT Falahee M. Reviewer Report For: Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis [version 1; peer review: 2 approved, 2 approved with reservations]. NIHR Open Res 2023, 3:29 (https://doi.org/10.3310/nihropenres.14554.r31360) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-31360 https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-31360 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Views 0 How to cite this report: Shedden-Mora MC. Reviewer Report For: Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis [version 1; peer review: 2 approved, 2 approved with reservations]. NIHR Open Res 2023, 3:29 (https://doi.org/10.3310/nihropenres.14554.r29368) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-29368 https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-29368 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 20 Jul 2023 Approved VIEWS 0 This protocol describes the planned meta-analysis of studies within trials (SWATs) comparing standard patient information leaflets (PILs) with a new approach, the principled patient information leaflets (PrinciPILs). PrinciPILs aim to overcome the risks of standard PILs of eliciting nocebo effects ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close This protocol describes the planned meta-analysis of studies within trials (SWATs) comparing standard patient information leaflets (PILs) with a new approach, the principled patient information leaflets (PrinciPILs). PrinciPILs aim to overcome the risks of standard PILs of eliciting nocebo effects by specifically presenting side effect information in an improved way. The protocol is generally really well described and precise. However, there are some issues that could help the reader to better understand the overall approach. Moreover, I have some methodological questions, as outlined below. The protocol is generally really well described and precise. However, there are some issues that could help the reader to better understand the overall approach. Moreover, I have some methodological questions, as outlined below. - Introduction: It would really help the reader to provide some more information on the PrinciPILs, and on how they differ from standard PILs. - Information sources: If I understand correctly, the primary author of this protocol has been involved in all SWATs of PrinciPILs. As the authors are probably aware of the number of SWATs conducted, it would be helpful to state this number here (although normally not common in protocols). - Outcomes and prioritization: What is the primary outcome, what are the secondary outcomes? Will the primary outcome be overall adverse events or side effect burden reported in the PrinciPILs groups, compared to standard PILs? It would be helpful to be more precise. - Outcomes and prioritization: Nocebo effects are more pronounced in nonspecific side effects such as headaches, fatigue or dizziness, compared to specific side effects, (e.g., fever after vaccination). I suggest that you could consider to define nonspecific side effects or symptoms across the SWATs, compared to specific side effects. This might give you a clearer picture on how PrinciPILs can improve nocebo effects. - Data synthesis: I was wondering whether the authors have considered to perform patient level meta-analysis. If I understand correctly, the authors have all patient-level data at hand. This could provide a much clearer picture of potential nocebo effects. - Is the rationale for, and objectives of, the study clearly described? Yes - Is the study design appropriate for the research question? Yes - Are sufficient details of the methods provided to allow replication by others? Yes - Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: placebo and nocebo effects, treatment expectations, persistent physical symptoms, somatic symptom disorder CITE HOW TO CITE THIS REPORT Shedden-Mora MC. Reviewer Report For: Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis [version 1; peer review: 2 approved, 2 approved with reservations]. NIHR Open Res 2023, 3:29 (https://doi.org/10.3310/nihropenres.14554.r29368) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-29368 https://openresearch.nihr.ac.uk/articles/3-29/v1#referee-response-29368 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. 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