The formulation of clinical questions is a critical starting point in the development of Clinical Practice Guidelines (CPGs), directly influencing their scope and recommendations. Although various health organizations have issued numerous guideline development manuals, their guidance on the specific processes and operational methods for formulating clinical questions remains generally insufficiently detailed. This often leads to misunderstandings and operational difficulties for guideline developers in practice.

To compare the methodological content related to the formulation of clinical questions in authoritative guideline development manuals from both domestic and international sources, and to provide insights and references for constructing a more systematic and operational clinical question formulation process.

The system systematically retrieved guidelines and manual development documents published by authoritative domestic and international institutions, with a search period spanning from January 2010 to May 2025. Data were screened based on clearly defined inclusion and exclusion criteria. Using a directed content analysis approach, the study employed the seven-step framework of WHO manuals as an analytical framework to encode, extract, and conduct summary analyses of clinically relevant content identified in the 11 included manuals. Comparative analyses were performed on key elements and processes.

A total of 11 manuals were included, comprising those from the WHO, the National Institute for Health and Care Excellence (NICE) in the UK, the Scottish Interhospital Guidelines Network (SIGN), and the Manual on Acupuncture in Traditional Chinese Medicine [World Federation of Acupuncture Societies (WFAS), National Administration of Traditional Chinese Medicine (NATCM)]. Comparative analysis revealed that all manuals recommended the use of the PICO framework for problem formulation, but differences existed in the definition and application of core concepts such as "scope","issues"and "problems". Only a few manuals provided step-by-step procedural recommendations, while most offered only general guidelines. Regarding the sources of clinical questions, clinical surveys and literature reviews were included. In terms of outcome measure importance evaluation, manuals such as WHO explicitly adopted a 9-point scoring system.

Current guideline manuals provide insufficient guidance in terms of standardization and refinement for the clinical question formulation stage. Future efforts should focus on constructing a systematic, step-by-step operational framework that integrates multi-source clinical question collection, PICO-structured formulation, pre-assessment of evidence quality, and incorporation of patient values. Through systematic comparison, this study clarifies the key components and directions for building such a framework, offering direct methodological references for enhancing the scientific rigor, practicality, and efficiency of guideline development.