An analysis of international strategies for monitoring and preventability described in medicinal product information: a study protocol

Introduction: Product information is intended to be a reference for healthcare professionals to verify instructions for monitoring and preventability of adverse drug reactions (ADRs), among other things. International comparisons of these documents, using the Systematic Information for Monitoring (SIM) method, have highlighted discrepancies in the instructions for monitoring, but there has been no comparison of preventability instructions. Objectives: To quantify and compare, across different countries, the completeness of instructions for monitoring and preventability provided to healthcare professionals in medicinal product information. Methods: We shall retrieve information included with medicinal products that have been involved in signals communicated by regulators, in 2014-2019 and based on clinical assessments of reports of ADRs, from the websites of 35 regulatory agencies. We shall evaluate the completeness of instructions for monitoring using a modified version of the SIM method; a score of 67% will qualify a monitoring instruction as sufficiently complete. To evaluate the completeness of instructions for preventability, we have derived a framework from the Dose-responsiveness-Temporality-Susceptibility (DoTS) classification of ADRs and related implications, comprising domains and items/implications. We shall iteratively develop a threshold to define the sufficiency of completeness of instructions based on data distribution across DoTS domains. We shall present descriptive statistics by country for each item of the framework and by total scores, using tables, or figures where necessary. Outcomes: Our target audience is regulators, and the results should highlight gaps in the level of information available to healthcare professionals. This study may also provide some insights into how suspicions of causality that arise from clinical assessments of reports of ADRs translate into actionable recommendations in clinical practice. ### Competing Interest Statement All authors have completed the International Committee of Medical Journal Editor forms. This work is part of DS's DPhil in Evidence-Based Health Care at the University of Oxford, funded by the Uppsala Monitoring Centre (DS's employer). No undue influence or coercion was exerted on DS by the funder throughout the design and conception of the study, or the writing of this protocol. DS, IJO and NN have no relevant conflicts of interest. JKA has published papers and edited textbooks on adverse drug reactions and has published papers dealing with the definitions of relevant terms. ### Funding Statement Please, see competing interests. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes We will abide by data availability requirements of the journal to which we will submit the study this protocol describes. If there are no specific requirements, all data produced by the study described in the protocol will be made available upon reasonable request to the authors.