The generation of synthetic clinical trial data offers a promising approach to mitigating privacy concerns and data accessibility limitations in medical research. However, ensuring that synthetic datasets maintain high fidelity, utility, and adherence to domain-specific constraints remains a key challenge. While hyperparameter optimization (HPO) improves generative model performance, the effectiveness of different optimization strategies for synthetic clinical data remains unclear. This study systematically evaluates four HPO objectives across nine generative models, comparing single-metric to compound metric optimization. Our results demonstrate that HPO consistently improves synthetic data quality, with Tab DDPM achieving the largest relative gains, followed by TVAE (60%), CTGAN (39%), and CTAB-GAN+ (38%). Compound metric optimization outperformed single-metric objectives, producing more generalizable synthetic datasets. Despite improving overall quality, HPO alone fails to prevent violations of essential clinical survival constraints. Preprocessing and postprocessing played a crucial role in reducing these violations, as models lacking robust processing steps produced invalid data in up to 61% of cases. These findings underscore the necessity of integrating explicit domain knowledge alongside HPO to generate high-quality synthetic datasets. Our study provides actionable recommendations for improving synthetic data generation, with future work needed to refine metric selection and validate findings on larger datasets.

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