The International Application and Standardization of Chinese Medicine for Preventing and Treating COVID-19: An Analysis of International Clinical Guidelines and ISO Standards

Traditional Chinese Medicine (TCM) has been widely used for preventing and treating the Coronavirus Disease 2019 (COVID-19) in China [1]. In 2022, Chinese experts shared the research data and clinical experience in using TCM for COVID-19 with World Health Organization (WHO) experts and gained recognition. An expert meeting report from WHO found encouraging data to suggest that TCM was beneficial in reducing the risk of progression from mild-to-moderate cases to severe COVID-19 and recommended to Member States to consider the potential use of TCM [2]. In addition to the clinical research, the mechanism studies on TCM preventive and therapeutic effects, such as research on the Huoxiang Zhengqi oral liquid [3], Qingfei Paidu decoction [4-6], Xuebijing injection [7], Lianhua Qingwen capsule [8,9], showed antiviral and anti-inflammatory abilities against the novel coronavirus. 

It is necessary and urgently to prompt the development of international standards of Chinese material medica for the treatment of COVID-19 to ensure the quality and safety of herbal medicines for international use. ISO/TC 249, the 249^th technical committee of International Organization for Standardization (ISO), is focused on standardization of TCM including single herbal medicine [10]. Thus, this research explored of the international application of herbal medicines through analysis of international clinical guidelines of COVID-19 and found international standardization of commonly used single herbal medicines in ISO/TC 249.

• Data sources 

Traditional Chinese medicine -- Priority list of single herbal medicines for developing standards (ISO/TR 23975:2019) [11] is a consensus and main reference for standardization of Chinese materia medica in ISO/TC 249. This included herbal medicines from pharmacopoeias (or similar official documents) of seven countries (regions and international organizations), China, Hong Kong, Japan, Republic of Korea, European Union, United States and Thailand, in which TCM was widely used and officially regulated. Thus, the official sites of health departments and industrial associations of the seven members of ISO/TC 249 were searched for eligible guidelines. 

• Inclusion criteria

Clinical Practice Guidelines (CPGs) recommended herbal medicines for preventing, treating and/or recovering from COVID-19, issued by the health department of the government was included. If there were no officially issued guidelines, the documents developed by industrial associations were eligible. 

• Extraction of herbal medicines with international application 

The herbs formulae and manufactured products recommended by CPGs were recorded, and the components of the patent medicines were extracted according to relevant pharmacopoeia or the drug labels of the manufacturers.

The single herbs retrieved were computed and analyzed. The herbs used in at least two guidelines from different countries (regions and international organizations) were included and the frequencies were summed. 

• Exploration of the international standardization of included herbs 

The existing ISO standards and standard projects (approved standard proposals) of extracted herbal medicines were searched on the ISO/TC 249 website (till December 31, 2022) and the preliminary working items (PWIs, i.e., unapproved standard proposals) information was obtained from the ISO/TC 249 National Mirror Committee in China. The herbs without standard (project or PWI) were ranked based on ISO/TR 23975:2019.

• Included guidelines 

Four treatment guidelines of COVID-19 were explored, 2 from China [12,13] and 2 from Korea [14-16]. Both Chinese CPGs issued by the National Health Commission of China, one was for treatment and the other for rehabilitation. The two Korean guidelines were developed by the Association of Korean Medicine and the Korean Association of Traditional Pulmonary Medicine separately and both referenced the Chinese treatment guideline. Although there was no similar guideline in Japan, the Japanese Association for Infectious Diseases translated the treatment Chinese guideline, Diagnosis and Treatment Protocol for COVID-19 (Trial Version 9) [17, 18]. 

• International application of herbal medicines 

Of all the 4 guidelines, there were 62 herbal formulae and manufactured products which comprised of 284 single herbs. In the frequency analysis of these herbs, Glycyrrhizae Radix et Rhizoma (Gan Cao) was found to be the herb with the highest frequency of usage in all the Chinese and Korean guidelines (Table 1). 

Table 1: Herbal medicines of the included clinical practice guidelines. 

After merging the same herbs, all together 78 herbs were both used in the guidelines from the two countries and the top 5 frequently used medicines were Glycyrrhizae Radix et Rhizoma (Gan Cao), Pinelliae Rhizoma (Ban Xia), Scutellariae Radix (Huang Qin), Armeniacae Semen Amarum (Ku Xing Ren), Citri Reticulatae Pericarpium (Chen Pi) (Table 2). 

Table 2: Single herbs used both in the Chinese and Korean guidelines.

*Note: The Latin name of the herbs were based on the 11^th edition of the Chinese Pharmacopeia.

#Note: Herbs were not included in the 11th edition of the Chinese Pharmacopeia. 

• International standardization of herbal medicines 

Of the 78 herbs included, 17 were standardized with published standards (under development) and 5 had proposals in ISO/TC 249 work programs (Table 3). Checked in the ISO/TR 23975:2019, 11 of the 56 herbs unstandardized were not recorded and the ranking list of rest herbs was shown in table 4. Nine herbs of the ranking list belonged to the top 100 single herbal medicines and in high priority according to the ISO/TR 23975:2019. 

Table 3: International standardization of included herbal medicines. 

*Note: The Latin name of the herbs were based on the 11^th edition of the Chinese Pharmacopeia. 

Table 4: Ranking list of for ISO standardization. 

*Note: The Latin name of the herbs were based on the 11^th edition of the Chinese Pharmacopeia.

Two countries used herbal medicines for preventing and treating COVID-19 and four guidelines were included. 22 of the 78 eligible single herbs were standardized or in work plan of ISO/TC 249 and 45 of the rest herbal medicines were suitable for future international standardization. However, only 9 unstandardized herbs in high priority of the ranking list. 

Compared with 194 Member States of WHO, the international application of Chinese medicine for preventing and treating COVID-19 is quite limited. There is still a long way for Chinese medicine to participate in international cooperation on the prevention and treatment of major infectious diseases. 

TCM was the first traditional medicine acquired WHO recognition for treating COVID-19 which was a milestone and could not be overstated. The TCM for COVID-19 were used in China and Korea and got support from Japan, the three countries were all important Participating members in ISO/TC 249, which showed great global relevance. The international standardization of herbs treating COVID-19 is in urgent need. 

However, the main document for herbal medicine standardized planning in ISO/TC 249, ISO/TR 23975:2019, published before the outbreak of COVID-19, cannot fully adapt to the new international situation. 28% (22/78) of the Republic of Korea and China used herbal medicines for preventing and treating COVID-19 has been standardized. Only 20% (9/45) of unstandardized herbs in high priority of ISO/TR 23975:2019 and 24% (11/45) even did not included. In addition, the pandemic also changed the international trading value of many herbal medicines, which was one of the main developing principles of the ISO/TR 23975:2019. It is time to revise and update ISO/TR 23975:2019. 

The international application and standardization of the manufactured products for COVID-19 was even worse. Only the Chinese treatment guideline included applied 16 Chinese patent medicines and no foreign manufacturers of these medicines. Thus the Chinese patent medicines had to be decomposed into single herbs in analysis.

The results showed narrow scope of international application and low degree of international standardization in using Chinese medicine to prevent and treat COVID-19. More efforts are needed from the international colleagues.

The authors sincerely thank three Korean experts (Professor Myeong Soo Lee from the Korea Institute of Oriental Medicine, Professor CHOI Jun-Yong from Korean Medicine Hospital of Pusan National University and the School of Korean Medicine, Pusan National University, and Researcher Lin Ang from the Korea Institute of Oriental Medicine) for offering the compositions of several Korean formulae in the included Korean guidelines.

The authors declare that they have no competing interests.

This work was supported by the International Corporation Project of the National Administration of Traditional Chinese Medicine (Grant No.0610-2240NF021550).

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