The early approval threshold for TCM injections was low, and most TCM injections had no thorough research on safety and efficacy [18]. In recent years, TCM injections have been questioned a lot because of frequent ADRs. Due to serious adverse events, the government must pay more attention to the quality problems of TCM injections. According to the Opinions on Deepening the Reform of the Review and Approval System and Encouraging the Innovation of Drugs and Medical Devices released in 2017, for the purpose of evaluating both chemical and TCM injections in safety, efficacy, and quality controllability, enterprises must conduct the comprehensive research at approval, and the post-marketing researches, including the active ingredients, mechanism of action, and clinical efficacy [7].

Recently the re-evaluation of TCM injections has achieved certain positive results. For example, the ADR proportion caused by TCM injections has decreased continually since the rigorous requirements for the injections in approval and re-valuation were proposed in 2017 (Fig. 2). Moreover, up to July 11, 2022, the Announcements issued by NMPA revised the contents of instruction manuals for 31 kinds of TCM injections [32]. These fully affirm the validity and necessity of re-evaluation. The enterprises should evaluate and improve the quality of TCM injection products as soon as possible following the relative regulations and policies (Table 2).

Table 2 Comparisons between the TCM injection regulation status and the requirements for general injectionsDemonstrate safety and effectiveness with scientific evidence

Efficacy is the key to a drug. Usually, a drug must be evaluated in strict scientific clinical trials with hundreds to thousands of patients. However, due to the low level of research and limited technical conditions at the early stage, most TCM injections did not undergo rigorous clinical trials before approval [33]. Up to July 6, 2022, only 21 kinds of TCM injections among 128 approved TCM injections had relevant clinical trial information in the ClinicalTrials.gov database [34].

In clinical practice, TCM injections are mostly used in combination with other chemical drugs. For instance, among 4382 cases associated with the Shuanghuanglian injection in the clinic, 82.79% of injections were used in combination with antibiotic drugs [35]. It is quite necessary to use reliable and scientific evidence to evaluate the efficacy of TCM injections being used alone [36]. If the real efficacy of TCM injections is not clear, it is hard to distinguish their real contribution to combination therapies.

Identifying the material basis of TCM injections is a prerequisite for evaluating clinical efficacy and safety. In 2006, the Basic Technical Requirements for Traditional Chinese Medicine and Natural Medicine Injection made requirements on the ingredients of TCM injection [5]: for injections made of active ingredients, the content of a single ingredient should be no less than 90%; for multi-component TCM injections, the content of well-defined components in the total solids should be no less than 60% and the measurable components should be no less than 80% of total solids; raw materials, intermediates and preparations should be studied to establish fingerprints respectively, and the correlation study between them should be carried out; the components whose structure is clarified should be reflected in the fingerprint, generally not less than 90% of clarified components. These requirements are collectively called 689 Principle. A previous review summarized that some TCM injections have satisfied the requirements of 689 Principle, some even with higher standards [37]. For example, a company claimed on its website that they have completed a study of the material basis of Tanreqing injection: among the total solids of Tanreqing injection, the structures of over 80% of components are well-defined, over 80% of components are measurable, and 93% of the well-defined components can be identified in the fingerprints [38].

Pharmacokinetic studies investigate drug action mechanisms and in vivo processes, which can provide scientific guidance for clinical uses. In recent years, some pre-clinical and clinical pharmacokinetic studies have been carried out for the re-evaluation of TCM injections. However, most of them focused on pre-clinical research, while only a few studies related to clinical studies [19]. It is well-known that the clinical pharmacokinetic study in the human body is of great significance for the safety and effectiveness of a drug in clinical uses. Thus, more large-scale and standardized clinical trials of TCM injections should be carried out in the future.

Evidence-based medicine is another powerful method for evaluating the efficacy of TCM injections. A number of TCM injection studies related to randomized control trials (RCTs) and meta-analysis were published every year [39,40,41]. Danhong injection (DHI) is a kind of multi-target drug. To evaluate the efficacy and safety of DHI to treat symptomatic chronic stable angina, a rigorously designed randomized controlled trial was conducted in 920 patients with moderate symptomatic stable angina. The results showed that after 14-day of DHI use, the angina episodes were significantly reduced and without any additional risk. The follow-up visit found that the health condition specific to angina was improved for at least 90 days. This study further identified the anti-angina therapeutic modules of DHI on the effective population by developing a systemic modular approach. This approach will be helpful to facilitate the modernization of Chinese medicine in confirming therapeutic effects and revealing therapeutic mechanisms [40]. Moreover, the professional TCM clinical evidence database (EVDS) which has been established in 2016 can act as a very powerful tool to provide a reference for the TCM injection clinical effectiveness evaluation [42].

Strengthen the quality management of raw herb materials

As one of the dosage forms with the highest quality requirements, TCM injection is required higher standards of consistency and controllability than other traditional Chinese medicine products. As the important raw materials for TCM injection production, the quality of medicinal plant raw materials should be controlled first.

In 2002, the first Quality Management Standards of Chinese Herbal Medicine was released to control the quality of herb medicine by using Good Agricultural Practice (GAP) [43]. GAP is the basic criterion to standardize the production and management of Chinese herbs, and regulates the processes of herbs such as collection, storage, and processing. As of February 2016, 167 kinds of Chinese herbal medicines from 129 companies have passed the GAP certification [44]. But this GAP was canceled in 2016 because it played a limited role in the continual management. In 2022, the new GAP certification was released to further promote the standardized production of Chinese herbal medicine [45]. Compared with the old version of GAP, the newly released GAP further refines the whole process of quality management in Chinese herbs. Enterprises should strengthen their management of the quality of raw materials from the herb source by new GAP standards.

Modernize the preparation processes and improve the quality control

Most enterprises still adopt outdated methods and low-standard quality control. To ensure high-standard and controllable production processes, enterprises should speed up their transformation to more advanced and scientific production processes. In 2016, the NMPA clarified the requirements for enterprises to achieve drug traceability [46]. The quality traceability system refers to recording the drug information from manufacture to market to quickly and effectively trace any quality issues. A good traceability system is very important to the quality management of TCM injections. For example, although the Xiyanping injection has completed a large number of non-clinical safety and pharmacology studies and post-marketing clinical safety studies from 2009 to 2013 [47], this TCM injection was still urgently recalled for causing severe adverse reactions such as chills and fever in 2017 [48]. This gives us enlightenment that a one-time evaluation cannot ensure the life-long safety of a drug, and safety evaluation should be a systematic project that runs through the entire life cycle of TCM injections.

Pharmacoeconomics evaluation of TCM injections

The purpose of the pharmacoeconomic evaluation is to rationally select and use drugs to achieve efficient, safe, and economical use of limited medical and health resources to get the optimal treatment effect and the minimal economic burden. TCM injections occupy a huge share of the TCM market compared with other dosage forms of TCMs, accounting for one-third of the total TCM sales in hospitals [49]. while the therapeutic effects of TCM injections in clinical use do not match the high investment. For example, one study showed that the cost of Shuanghuanglian injection and Qingkailing injection was nearly 10 to 30 times higher than that of oral dosage forms when obtaining the same therapeutic effect [50]. In order to effectively control unnecessary drug costs, on the one hand, the clinical cost and effectiveness of commonly used TCM injections in National Basic Medical Insurance should be investigated to compare with other alternative dosage forms. On the other hand, the cost of ADR treatment from TCM injections should be monitored too.