Establishment Of Grading Standards For Adverse Events Of Traditional Chinese Medicine Injections And Optimization Of Causal Relationship Determination Method

Background:Traditional Chinese medicine(TCM)injections,as a modern therapeutic approach in TCM,play a significant role in the treatment of cardiovascular and cerebrovascular diseases,tumors,and infectious diseases.Their unique efficacy and rapid pharmacological effects have led to widespread clinical application.However,with increased usage,associated safety concerns have become more prominent.Current safety evaluations of TCM injections reveal inadequacies in quality control,terminological definitions in clinical research,severity assessment of adverse drug reactions,and causality determination,despite numerous policies and guidelines issued by the National Medical Products Administration.In clinical research,the definition and classification of adverse events and reactions of TCM injections are subjective and confusing,with unclear criteria for severity assessment,leading to inconsistent evaluation results.These issues affect the scientific and reliability assessments of TCM injections,thereby impacting patient safety and medication decisions.Moreover,the insufficiency in detailing adverse reaction information in the instructions of TCM injections hinders clinicians from determining the relative risks of their use.Therefore,establishing a grading standard for adverse events of TCM injections and a tool for causality determination is urgently needed to ensure patient medication safety and rational clinical application of TCM injections.Objective:This study aims to address the current issues in safety evaluation of TCM injections,particularly the ambiguities in adverse event grading and causality determination,by developing a suitable evaluation system.The main objectives include:Establishing a grading standard for adverse events of TCM injections:By analyzing and comparing existing adverse event grading systems and considering the characteristics and clinical application of TCM injections,a specific grading standard is developed.This aims to provide clear classification and severity assessment guidelines,reducing subjectivity and inconsistency in existing evaluation systems.Developing a tool for determining the causality of adverse events of TCM injections:Creating a simple,rapid,and relatively objective tool to guide clinicians and researchers in quickly and accurately determining causality of adverse events.This tool should distinguish the association between adverse events and TCM injections while excluding other possible causes.Finally,testing the practicality,reliability,and effectiveness of the new standards and tools through prospective clinical studies involving adverse events.Methods:Establishing Adverse Event Grading Standards The research began with literature review and extraction of information from instructions,comprehensively gathering adverse events associated with TCM injections,and standardizing and classifying these adverse event terms.Ambiguous and inconsistent terms were eliminated,and a unified terminology was adopted using MedDRA’s LLT as a reference.Adverse events were then categorized according to SOC.The process of constructing these standards was systematic and challenging.CTCAE5.0 was used as a reference due to its authority and international application,selecting relevant adverse events and preliminarily classifying them according to its standards.For TCM-specific or unlisted adverse events in CTCAE5.0,independent severity divisions were made,reviewed and revised by two clinical experts.In cases of disagreement between experts,a third expert was consulted.This grading table was further refined with the advice and review of multiple clinical department experts.Developing a Tool for Causality Determination The research began with selecting a checklist of questions,analyzing widely-used causality determination tools like the WHO-UMC system and Naranjo algorithm,assessing their applicability to TCM injections,and filtering out inapplicable or clinically impractical questions.A preliminary checklist for adverse event causality determination was formed,laying the groundwork for further discussion and optimization.Experienced clinicians,nurses,and clinical researchers were invited to provide input on their requirements for the tool,factors considered in determining causality,and feedback on the initial checklist.Questions were systematically categorized,clarifying different types of drug adverse reactions and forming a checklist prototype.An operational flowchart was developed to make the tool more intuitive and easy to use.Multiple rounds of internal validation were conducted by the research team,considering clinical experience and expert opinions to ensure the accuracy and logical coherence of question categorization.Results:1.Grading Standards for Adverse Events of Traditional Chinese Medicine InjectionsThe study provided a set of specific grading standards for adverse events of Traditional Chinese Medicine(TCM)injections,filling a gap in the objective assessment of the severity of safety evaluations for these injections.TCM injections often have complex components and preparation processes,differing from Western medicine,necessitating specialized evaluation methods.The establishment of these grading standards is instrumental in enhancing the level of safety evaluations for TCM injections,ensuring that patients receive more comprehensive safety information when using them.By aligning with international grading standards,this research facilitates the better integration of TCM injections into the global pharmaceutical research and regulatory framework.2.Constructing the Causality DeterminationDuring the summarization and selection phase,extensive literature research and expert discussions systematically addressed issues in causality determination of TCM injections,clarifying the study’s objectives and direction.The core issues were identified for targeted subsequent research.Various adverse events and causality literature were summarized and filtered to provide a solid foundation for the study.Semi-structured interviews with clinical experts in both Western and Chinese medicine were conducted to gain extensive clinical experience and professional knowledge.Their insights and experience were crucial for a deeper understanding of the study and problem-solving.The semi-structured interviews allowed for in-depth exploration of experts’ views,methods,and needs for causality determination,providing practical guidance and basis for tool construction.During the question categorization and optimization phase,the research team refined the checklist into specific items,categorizing and optimizing them.To clearly present the logical relationships of the checklist,a detailed flowchart was developed,ensuring logical consistency and ease of use for medical professionals.The flowchart provided clear guidance for tool use and helped reduce misjudgments and increase reliability.To facilitate rapid judgment by clinical practitioners,a brief mobile application tool was developed,based on the checklist’s logic and guidelines,enabling quick and accurate decision-making,providing a more convenient solution for TCM injection causality determination.Validating the Causality Determination Tool The new adverse event causality determination tool was compared and validated against the correlation assessment methods in the "Guidelines for Individual Case Safety Report Collection and Reporting." This validation study involved 17 adverse events,assessed by 7 evaluators.Using the traditional method,causality scores were classified as:1 case(1%)pending evaluation,8 cases(7%)possibly unrelated,38 cases(32%)possibly related,68 cases(57%)very likely related,and 4 cases(3%)confirmed related.Pairwise Kappa scores ranged from 0.25 to 0.71,indicating general interrater reliability(IRR),with a global Kappa score of 0.34(95%confidence interval:0.25-0.71).After assessing the same cases with the new tool,causality categories were classified as:64 cases(54%)consistent causality determination,28 cases(24%)uncertain,22 cases(19%)inconsistent causality,and 4 cases(3%)unclassifiable.The new tool’s pairwise Kappa scores ranged from 0.05 to 0.97,demonstrating good IRR,with an overall Kappa of 0.62(95%confidence interval:0.36-0.88).While traditional methods had Kappa scores ranging from 0.25 to 0.71,the new tool increased this score to 0.62.The new tool significantly improved consistency among evaluators by providing clearer guidance and assessment procedures,not only enhancing interrater consistency but also likely improving the accuracy of evaluation results.This is because the standardized assessment process reduced the interference of subjective judgments,making the evaluation results more objective and reliable.Conclusion Establishing objective adverse event grading standards and developing a simple and rapid causality determination tool can enhance the consistency of safety evaluations,reduce misreporting,better guide clinical decisions,improve patient safety,increase objectivity in judgments,accelerate therapeutic decision-making,reduce misdiagnoses and missed diagnoses,and support clinical research.These improvements will help address issues in the safety evaluation of TCM injections,enhancing their quality and safety,and providing better medical services for patients.