Challenges for Using RWE in TCM RegulationThe Complexity and Diversity of TCM Terminology

The diversity and complexity of TCM terminology have brought some obstacles to the quantification of TCM clinical information in the RWS. The standardization of TCM terminology needs further study, and the application of standardized results is insufficient and disjointed from clinical and scientific research [48, 49]. Therefore, how to standardize TCM terminology to meet the needs of information extraction in the RWS is an urgent problem to be solved.

Difficulties in Data Collection and Integration

Challenges of data collection and integration in TCM RWS[50,51,52,53,54,55,56]: (1) The data distribution of hospital medical records, ancient books of traditional Chinese medicine monographs, experience of famous old Chinese medicine practitioners, and other data are scattered. (2) Data standards are not uniform when establishing databases. (3) There is also the phenomenon of “data silos” (defined simply as isolated systems with limited external connectivity) in data sharing. (4) No unified universal data model nor semantic standard exists in China. (5) Patient engagement and data privacy protections are inadequate. (6) RWS, especially retrospective RWS, may have limitations in tracking long-term outcomes and assessing the durability of TCM interactions, such as high loss rate, incomplete, and inaccurate follow-up content.

Thus, it is difficult to avoid the problems of excessive data volume, unstructured data, data missing, and strong data heterogeneity in RWS.

Difficulties in the Quality Control of TCM RWS

TCM clinical practice has its own particularities, such as the complicated diagnosis and treatment modality of doctors based on syndrome differentiation and complex intervention of internal and external treatment, which all determine the particularity and difficulty of TCM RWS. There are few published reports of RWS on TCM that clearly specific quality control measures, which influenced the results of RWS reliability [57, 58].

Confounding and Bias Control Difficulties

Non-randomization of RWS inevitably results in confounding and bias, which may distort the true association between exposure and outcome. Confounding and bias control difficulties in real-world TCM studies arise from the complexity of interventions, heterogeneity of practice, lack of standardized protocols, patient self-selection bias, and limited control groups. Compared with chemical drugs and biologics, TCM may have more confounding and bias in RWS, such as the confounding and bias introduced in the complicated process of syndrome differentiation and treatment (syndrome, syndrome type, syndrome differentiation, drug use, etc.)[58, 59].

Limited Evidence Hierarchy

Compared to RCTs, RWE in TCM research is often considered lower in the evidence hierarchy [60, 61]. This can lead to challenges in gaining acceptance and recognition from regulatory bodies, healthcare professionals, and researchers. An important ‘challenge’ that is the risk that evidence generated using RWD is flawed, may leading to people being harmed. TCM RWS in China mainly focused on the analysis of the efficacy of Chinese medicine injections and big data-based clinical medication rule analysis, with the main research type of observational study [39]. RWE application and scientific nature need further improvement.

Future Directions and Opportunities for Using RWE in TCM Regulation

Given the potential benefits and challenges of using RWE in TCM regulation, there are several future directions and opportunities that can be pursued to further advance the field. These include the following:

Harmonizing and Standardizing TCM Terminology

The quantification and standardization of TCM clinical information is the foundation of TCM clinical information management. Studies have shown that TCM terminology (such as real-world clinical diseases of symptoms) will be the focus of future standardization research [62]. It is recommended to create a standard library of terminology specific to clinical research and to establish a research pathway for standardization of TCM terminology based on real-world research needs.

Data Collection and Integration

The collection and integration of TCM data is an important step of RWS. The inter-regional/inter-institutional information system connectivity, data standardization, and integrated data management should be promoted. The construction of TCM clinical research big data platforms is a realization method. At present, there are some shortcomings of the existing platforms. Regulatory Agencies are building digital platforms for real-world Chinese medicine research, accelerating the drafting of policy documents such as real-world Chinese medicine research guidelines and data collection standards [63, 64].

There is also proposed to innovate data collection models and explore diversified follow-up methods. For example, Guangzhou Greater Bay Area Real World Research Center of Traditional Chinese Medicine is the first research institution in China focusing on RWS of TCM based on family doctors and is exploring a new cooperation model of “inside and outside hospitals” for RWS, which is more conducive to obtain complete data, especially follow-up data [65]. The sponsors and this research institution should be responsible for making maintaining this data.

Patient engagement and data privacy are important considerations in the use of RWE in TCM regulation. Data privacy should be safeguarded through the use of secure data storage and transmission methods. In addition, it is suggested improving traceability to source data for transparency.

Data Quality Management and Standardization

The reliability of evidence is directly dependent on the quality of RWS conducted on TCM. When it comes to drug registration materials, it is essential to establish clear quality requirements for RWE. These requirements encompass various aspects, including basic prerequisites, organizational management, key pharmaceutical information, scientific research, risk management, ethical compliance, and study implementation [66]. To ensure standardized and high-quality RWS on TCM, it is crucial for regulatory authorities, applicants, research institutions, and researchers to collaborate to establish a robust research quality management system that aligns with the clinical characteristics of TCM.

Confounding and Bias Control

The more complex the research environment and data sources, the more complex the data processing and analysis techniques. On the one hand, relying on the TCM Regulatory Science Action Plan, there is an urgent need for interpreting RWS results with caution, and exploring methods to improve their scientific validity, reliability, and methodologies to control various biases. On the other hand, it is necessary to establish standardized and rigorous research design and statistical analysis, which puts higher requirements on sponsors and statistical experts.

Understanding and Rational Use of RWE

As RWE sources and analytics continue to advance, there has been new opportunities for using RWE in TCM regulation, such as RWE application scenarios mentioned above. Only RWD that meets the applicability, which is evaluated primarily by data relevance and reliability, can produce RWE. Compared with RCTs, RWE is not a lowering of standards; it can complement the evidence provided by traditional clinical trials to form a complete and rigorous evidence chain, rather than replace it.

In addition, education and training programs should also be developed to increase awareness and understanding of RWE among TCM practitioners, researchers, and regulators.