Comment & Response
September 18, 2023
Xuebijing Injection for Sepsis Treatment: When Will It Be Approved Outside of China?
Tianyang Hu
JAMA Intern Med. Published online September 18, 2023. doi:10.1001/jamainternmed.2023.4398
To the Editor A recent study by Liu and colleagues1 reported a reduction in 28-day mortality in patients with sepsis treated with Xuebijing (XBJ), a Chinese medicine compounded injection, compared with placebo. In fact, XBJ has been used in the Chinese market for almost 20 years since its approval in 2004, and it was approved by the National Medical Products Administration of China for the treatment of severe COVID-19 in 2020. However, there is still a long way to go before XBJ can be approved outside of China.
First of all, the docking and mutual recognition of national and international standards for proprietary Chinese medicines in mainland China is insufficient, and there are generally no international testing standards for proprietary Chinese medicines. As countries increase their regulation of medicines, registration regulations are becoming increasingly stringent. Therefore, it is increasingly difficult to register proprietary Chinese medicines in markets outside of mainland China because they are required to meet Western medicine standards. Individual proprietary Chinese medicines are even required to be registered as a “health food” or “food additive” when listed overseas. In short, policy support is still needed to obtain approval from drug regulatory agencies in countries and regions outside of China.
Second, given the complexity of the ingredients of proprietary Chinese medicines, there is still a lack of international standards for the evaluation of their safety and efficacy. For example, XBJ is composed of 5 Chinese herbs, including Paeoniae Radix Rubra, Chuanxiong Rhizuma, Salviae Militiorrhizae Radix et Rhizuma, Carthami Flos,and Angelicae Sinensis Radix, and it is difficult to precisely determine their pharmacologic, distribution, metabolic characteristics, and other attributes.
Third, network pharmacology is an important bridge between the scientific research of Chinese and Western medicines. A novel study2 attempted to elucidate the mechanism of action of XBJ in the treatment of sepsis based on this technique, identifying 4 key biologic functional modules, including inflammation, immunity, apoptosis, and coagulation, and found that the compounds in XBJ were associated with a reduction in the expression level of IL-1β and anti-inflammatory effects by regulating the NF-κB signaling pathway. However, these were only derivations based on computer technology. If it is true that network pharmacology can deduce the mechanism of action of proprietary Chinese medicines, would it be more effective to purify the active ingredients of XBJ and prepare them as a Western medicine for the treatment of sepsis?
Lastly, in the study by Dr Liu and colleagues,1 XBJ was compared with placebo and seemed to be associated with reduced mortality. However, there is still a lack of high-quality drug equivalence and noninferiority trials of XBJ. Therefore, it seems unlikely it would currently be the treatment of choice for patients with sepsis in countries and regions outside of China, and it would be difficult to get approval for emergency use.
A multicenter prospective randomized clinical trial of XBJ in countries and regions outside of China is urgently needed after completion of the rigorous review. Such a trial would verify the safety and effectiveness of XBJ in clinical settings beyond the Chinese population.
Comment & Response
September 18, 2023
Xuebijing Injection for Sepsis Treatment: When Will It Be Approved Outside of China?—Reply
Songqiao Liu, Jianfeng Xie, Haibo Qiu
JAMA Intern Med. Published online September 18, 2023. doi:10.1001/jamainternmed.2023.4395
In Reply We appreciate Dr Hu’s interest in and thoughtful criticism of our clinical trial.1 We agree that it will be challenging to get Xuebijing approved outside of China, but that the obstacles are surmountable.2
Our randomized clinical trial1 was carried out based on numerous early-stage scientific and pharmacological research projects. Xuebijing injection is created by combining traditional Chinese medicine with a number of different chemical compounds. The main components and pharmacokinetics of Xuebijing injection have been basically described.3 Preliminary preclinical studies have confirmed that Xuebijing injection has an antiseptic mechanism that includes anti-inflammatory, endothelial cell protection, regulating immune, and coagulation functions.4 A recent study5 showed that the main components of Xuebijing injection and antibiotics (etiologic treatment of patients with sepsis) worked very well together in terms of pharmacokinetic compatibility while treating sepsis. However, what remains unclear is which components of Xuebijing injection produced which effects and through which specific signal pathways. Regarding quality control, another study3 found very small batch-to-batch variability in the contents of the marker constituents of the main components of Xuebijing injection.
We do not think that drug equivalence or noninferiority trials are the next step because our study1 allowed for antibiotics and optimal sepsis management (eg, fluid resuscitation), and there is no well-accepted adjuvant treatment for sepsis. However, we do agree with Dr Hu that a large randomized clinical trial outside of China would be the best pathway to demonstrate the value of Xuebijing injection use in the rest of the world.
