Retrieval-Augmented Large Language Models for Clinically Aligned Adverse Event Coding in Acute Myeloid Leukemia Clinical Trials

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ABSTRACT Background Adverse event (AE) coding is essential for safety monitoring in oncology clinical trials, particularly in acute myeloid leukemia (AML), where intensive therapies are associated with frequent and heterogeneous toxicities requiring standardized MedDRA (Medical Dictionary for Regulatory Activities) coding. However, manual Low-Level Term (LLT) assignment remains labor-intensive, subjective, and difficult to scale. Although large language models (LLMs) have emerged as promising decision-support tools for automated coding, unguided zero-shot generation remains insufficient for reliable fine-grained MedDRA coding. Objective To develop and evaluate a retrieval-augmented reasoning pipeline for clinically aligned LLT-level MedDRA coding of free-text adverse events from prospective AML clinical trials. Methods We implemented a retrieval-augmented reasoning pipeline inspired by the retrieval-augmented generation (RAG) paradigm using LLaMA-3.3-70B-Instruct as the primary backbone and benchmarked the framework across multiple open instruction-tuned LLMs. Dense semantic retrieval first generated a constrained top-100 LLT candidate set for each AE, followed by structured LLM reasoning to select a single best-matching LLT and deterministic mapping to Preferred Term (PT) and System Organ Class (SOC) levels. The pipeline was evaluated retrospectively on AE datasets from three prospective AML clinical trials (MOSAIC, DELTA, and DaunoDouble) with automated LLT/PT/SOC metrics and expert-assessed Clinical Correctness Rate (CCR). Results Clinical expert review showed high clinical acceptability of the RAG pipeline across datasets (91-97%). Under automated evaluation, the pipeline achieved LLT exact accuracy of 50-58%, PT accuracy of 78-85%, and SOC accuracy of 90-93%. Zero-shot generation and random candidate selection performed substantially worse. Semantic retrieval more often included the coder-assigned LLT among the candidate terms available to the model than retrieval based on lexical similarity. Multi-model benchmarking showed that backbone choice mainly affected LLT exact agreement, whereas PT and SOC performance remained comparatively stable. Conclusions Retrieval-augmented reasoning supports clinically aligned MedDRA coding of free-text adverse events under realistic candidate constraints in AML clinical trials. Evaluation across three AML clinical trials showed that strict LLT-level string agreement underestimated clinical appropriateness, highlighting the importance of combining hierarchical evaluation metrics with clinical expert validation for AI-assisted MedDRA coding in hematology trials.

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