# Fine-grained List-wise Alignment for Generative Medication Recommendation

arXiv: https://arxiv.org/abs/2505.20218 · HTML: https://mlsanity.com/paper/2505.20218/

## Key facts

- Cited by 5 papers in the map (data through 14 Oct 2026).
- Builds on 21 of its 35 references that are in the map.
- First posted on arXiv 26 May 2025.

## Builds on (most cited first, 21 of 21)

- [Proximal Policy Optimization Algorithms](https://mlsanity.com/paper/1707.06347/) (2017)
- [DeepSeekMath: Pushing the Limits of Mathematical Reasoning in Open Language Models](https://mlsanity.com/paper/2402.03300/) (2024)
- [Direct Preference Optimization: Your Language Model is Secretly a Reward Model](https://mlsanity.com/paper/2305.18290/) (2023)
- [DAPO: An Open-Source LLM Reinforcement Learning System at Scale](https://mlsanity.com/paper/2503.14476/) (2025)
- [Large Language Models Encode Clinical Knowledge](https://mlsanity.com/paper/2212.13138/) (2022)
- [R1-VL: Learning to Reason with Multimodal Large Language Models via Step-wise Group Relative Policy Optimization](https://mlsanity.com/paper/2503.12937/) (2025)
- [From r to Q^*: Your Language Model is Secretly a Q-Function](https://mlsanity.com/paper/2404.12358/) (2024)
- [CoLLM: Integrating Collaborative Embeddings into Large Language Models for Recommendation](https://mlsanity.com/paper/2310.19488/) (2023)
- [GAMENet: Graph Augmented MEmory Networks for Recommending Medication Combination](https://mlsanity.com/paper/1809.01852/) (2018)
- [LLaRA: Large Language-Recommendation Assistant](https://mlsanity.com/paper/2312.02445/) (2023)
- [SafeDrug: Dual Molecular Graph Encoders for Recommending Effective and Safe Drug Combinations](https://mlsanity.com/paper/2105.02711/) (2021)
- [Change Matters: Medication Change Prediction with Recurrent Residual Networks](https://mlsanity.com/paper/2105.01876/) (2021)
- [CIRS: Bursting Filter Bubbles by Counterfactual Interactive Recommender System](https://mlsanity.com/paper/2204.01266/) (2022)
- [Conditional Generation Net for Medication Recommendation](https://mlsanity.com/paper/2202.06588/) (2022)
- [How Do Recommendation Models Amplify Popularity Bias? An Analysis from the Spectral Perspective](https://mlsanity.com/paper/2404.12008/) (2024)
- [Aloe: A Family of Fine-tuned Open Healthcare LLMs](https://mlsanity.com/paper/2405.01886/) (2024)
- [SPRec: Self-Play to Debias LLM-based Recommendation](https://mlsanity.com/paper/2412.09243/) (2024)
- [Leave No Patient Behind: Enhancing Medication Recommendation for Rare Disease Patients](https://mlsanity.com/paper/2403.17745/) (2024)
- [Process-Supervised LLM Recommenders via Flow-guided Tuning](https://mlsanity.com/paper/2503.07377/) (2025)
- [Natural Language-Assisted Multi-modal Medication Recommendation](https://mlsanity.com/paper/2501.07166/) (2025)
- [Fine-grained Alignment of Large Language Models for General Medication Recommendation without Overprescription](https://mlsanity.com/paper/2503.03687/) (2025)

## Built on by (most cited first, 5 of 5)

- [Medical Reasoning with Large Language Models: A Survey and MR-Bench](https://mlsanity.com/paper/2604.08559/) (2026)
- [Don't Start Over: A Cost-Effective Framework for Migrating Personalized Prompts Between LLMs](https://mlsanity.com/paper/2601.12034/) (2026)
- [SafeRx-Agent: A Knowledge-Grounded Multi-Agent Framework for Safe and Explainable Medication Recommendation](https://mlsanity.com/paper/2605.29146/) (2026)
- [RxEval: A Prescription-Level Benchmark for Evaluating LLM Medication Recommendation](https://mlsanity.com/paper/2605.14543/) (2026)
- [Teaching LLMs to Recommend and Defer in Underrepresented Epilepsy Care](https://mlsanity.com/paper/2606.31036/) (2026)

## Abstract (arXiv)

Accurate and safe medication recommendations are critical for effective clinical decision-making, especially in multimorbidity cases. However, existing systems rely on point-wise prediction paradigms that overlook synergistic drug effects and potential adverse drug-drug interactions (DDIs). We propose FLAME, a fine-grained list-wise alignment framework for large language models (LLMs), enabling drug-by-drug generation of drug lists. FLAME formulates recommendation as a sequential decision process, where each step adds or removes a single drug. To provide fine-grained learning signals, we devise step-wise Group Relative Policy Optimization (GRPO) with potential-based reward shaping, which explicitly models DDIs and optimizes the contribution of each drug to the overall prescription. Furthermore, FLAME enhances patient modeling by integrating structured clinical knowledge and collaborative information into the representation space of LLMs. Experiments on benchmark datasets demonstrate that FLAME achieves state-of-the-art performance, delivering superior accuracy, controllable safety-accuracy trade-offs, and strong generalization across diverse clinical scenarios. Our code is available at https://github.com/cxfann/Flame.