Abstract

Tuberculosis-related clinical trials in the West were a critical site of trial innovation throughout the twentieth century. And tuberculosis treatment articles and trials, from the late 1940s onward, would likewise serve as a key and instructive example of the uptake and development of clinical trial methodology in mainland China. The first tuberculosis RCT in China was published in 1963. By the late 1970s, large-scale and multi-center studies were conducted and published in mainland China. In the 1990s, randomized controlled trials integrating traditional Chinese and Western medicine in tuberculosis treatment began to emerge. This study aims to provide readers with insights concerning the development of RCTs in China from the 1940s to the 1990s through a detailed examination of tuberculosis treatment trials.

Introduction

The general history of the randomized controlled trial (RCT) in China reveals the scattered uptake of RCTs in the 1960s, followed by more robust expansion from the late 1970s, after the Cultural Revolution (Yu, Chen, and Podolsky 2025).  Starting from the 1990s, large-scale multicenter RCTs began to be conducted and published. Yet such a general overview leaves important topics to be further examined, including a more precise accounting of the timing and manner of the incorporation of RCTs within medicine in mainland China, the relationship between China and the West in this respect, and the relationship between conventional medicine and Traditional Chinese Medicine (TCM).

Tuberculosis-related clinical trials in the West were a critical site of trial innovation throughout the twentieth century (Marks 1997; Gabriel 2014; Chalmers 2005). For instance, the 1948 British Medical Research Council (MRC) assessment of streptomycin for tuberculosis was recognized as a landmark in the history of RCTs because it provided detailed information about the trial and the steps taken to prevent foreknowledge of treatment assignments (Medical Research Council 1948; Chalmers 2005). Subsequently, from the 1950s to the 1990s, the British MRC guided and conducted a series of tuberculosis-related RCTs in Great Britain and its colonial and post-colonial territories, such as India, Hong Kong, and East Africa (Fox, Ellard, and Mitchison 1999). And tuberculosis treatment articles and trials, from the late 1940s onward, would likewise serve as a key and instructive example of the uptake and development of clinical trial methodology in mainland China.

Several findings emerge from an examination of the Chinese medical literature. First, starting in the late 1940s, Chinese researchers engaged with western writings (especially from the United States and the United Kingdom) on the treatment of tuberculosis, including western RCTs of emerging therapeutics. Second, starting in the early 1960s and hence well before larger-scale interest in RCTs in China from the late 1970s onward (Yu, Chen, and Podolsky 2025), Chinese researchers began conducting RCTs of therapeutic regimens for tuberculosis. Third, such efforts ultimately took place not only in the context of the relationship between mainland China and Hong Kong, but in the context of the relationship between western antimicrobials and TCM, though such relationships (as well as the relationship of tuberculosis researchers and those evaluating therapies for other diseases) certainly merit further investigation. A summary of this history is provided in Table 1, before we consider such development in more detail.

 

From the West to China: Translating and Disseminating the Results of Clinical Trials for Tuberculosis Treatment

Through a review of early Chinese-language literature related to tuberculosis clinical trials, especially those published from the 1940s through the 1950s, it becomes evident that post- World War II clinical trials conducted in Western countries to assess the efficacy of tuberculosis drugs were translated and summarized by Chinese scholars in reputable journals[1].

For example, from the late 1940s and early 1950s onward, Chinese scholars began translating and publishing relevant material from Western publications on streptomycin treatment for tuberculosis. Initially, these publications were primarily translations of observational studies. The 1946 JAMA paper titled “Treatment of Tuberculosis with Streptomycin: A Summary of Observations on One Hundred Cases” (Hinshaw, Feldman, and Pfuetze 1946), was translated by Conghou Guo[2] and published in 1948 in the National Medical Journal of China (Guo 1948). Two years later, the American Medical Association’s Council on Pharmacy and Chemistry published in JAMA its summary of the Veterans Administration’s (VA) collaborative study of streptomycin in tuberculosis (Council on Pharmacy and Chemistry 1948). While the VA study was not a “controlled” study per se, it entailed some comparative components relating to differing doses of streptomycin employed among the 2780 patients to that point[3]. Yet in the article’s translation by Yannan Zhu and colleagues[4] in 1950 in the National Medical Journal of China (Zhu, Zhang, and Tang 1950), only the key findings were presented, with no introduction provided to the research methods employed. Finally, the 1949 JAMA review on “Streptomycin in the Treatment of Tuberculosis” (Pfuetze and Pyle 1949) (in which the classic 1948 British MRC streptomycin trial was not cited) was translated and published in 1950 in the Chinese Journal of Internal Medicine (Streptomycin in the Treatment of Tuberculosis 1950)[5].

In addition to straightforward translations of foreign-language literature, Chinese scholars in the late 1940s and early 1950s began to synthesize overseas clinical research results, with some references made to controlled trials. In 1949, Yang and colleagues at the Institute of Pharmacology at the National Shanghai Medical School published an extensive report in the National Medical Journal of China on the drug treatment of tuberculosis, particularly focusing on para-aminosalicylic acid (PAS). The report provided a review of various aspects, including the physical and chemical properties of PAS, laboratory experiments, animal studies, the relationship between chemical structure and therapeutic action, pharmacological considerations, and ultimate clinical application (Yang and Zhang 1949). The article presented results from experiments conducted in Sweden and the United Kingdom in the clinical application section; and while the majority were case reports, with no elaboration on the methods used by the original authors, as a key exception, the article did cite a Scandinavian study in which 11 PAS-treated patients were compared to equivalent control cases (“motsvarande kontrollfall”; it was unstated precisely how that control group was formulated) (Alin and Difs 1947). Similarly, in 1951, Guanqing Kan from the Beijing Municipal Public Health Bureau reported on the preliminary results of a controlled clinical trial on streptomycin therapy for pulmonary tuberculosis, as presented in January 1951 at the 10th Streptomycin Committee Meeting in the United States (Kan 1951)[6].

Of note, we have found no translated or summarized versions of the British MRC’s 1948 randomized controlled trial of streptomycin treatment for pulmonary tuberculosis. Instead, the attention of Chinese scholars gradually shifted to the British MRC’s work when the British MRC began using isoniazid to treat pulmonary tuberculosis in 1952 and reported a series of controlled trial results. Various scholars translated these results into Chinese and published them in different journals. In 1953, Delong Su (highlighted in Yu, Chen, and Podolsky 2025) from the School of Public Health at the First Medical College of Shanghai (now Fudan University School of Public Health, Shanghai, China) and Yingji Mao from Zhejiang Province Jinhua Hospital separately translated the results of the British MRC’s randomized controlled trial of isoniazid treatment for pulmonary tuberculosis (published in the BMJ in 1952) (Medical Research Council 1952) in the National Medical Journal of China (Su 1953) and Chinese Journal of Internal Medicine, respectively (Mao 1953). Su provided a brief summary of the methods used in the British MRC’s RCT:

The main focus of this trial was to compare the efficacy of the isoniazid and streptomycin regimen with the PAS combination therapy. Participants were divided without any subjective physician selection; instead, they were randomly assigned using a prearranged list based on random sampling numbers. The 331 participants were categorized into three groups based on their medical condition, age, and prior treatment history, with the proportions of both treatments being approximately equal within each group.

Compared to Su, Mao did not provide a description of the randomized, controlled methods used in the British MRC trial. Instead, Mao only described the number of participants, the trial duration, disease classification, and dosage.

That same year, Jinyuan Zhang from Beijing Tongren Hospital reported the results of the second report of the British MRC’s RCT of isoniazid treatment for pulmonary tuberculosis (Medical Research Council 1953a). While this translation provided a more detailed summary and translation of the British MRC’s RCT methods and results, it did not offer a comprehensive description of the controlled trial methods used by the British MRC. Instead, in the background, Zhang explained that the report encompassed 564 cases from 40 hospitals, treated over a period of three months. In his analysis of the original article’s section outlining the trial plan and methods, a general method was provided, including that all patients required a preliminary week of observation after admission, the categorization of applicable cases into three lesion types, and the dosages for the three treatment groups (Zhang 1953). The British MRC’s original publication itself outlined their randomization method (“When a patient has been accepted for the trial, treatment is allocated by the Tuberculosis Research Unit from confidentially held prearranged lists based upon random sampling numbers.”). However, Zhang did not mention this method in the translation.

In 1955, the Chinese Journal of Internal Medicine published the results of the British MRC’s “fifth report,” of its RCT of Isoniazid in combination with streptomycin (SM) versus with PAS in the treatment of pulmonary tuberculosis (Medical Research Council 1953b). Xianming Sun[7] translated this trial, and in the methods section only mentioned the types of patient cases, the different treatment methods in each group, and the allocation of cases in each treatment group. Regarding the allocation method, Sun provided a brief explanation of randomly assigning participants to the four groups. However, the translation did not specify the method used for randomization to each group (the original text again mentioned that treatment was allocated by the Tuberculosis Research Unit from confidentially held prearranged lists based upon random sampling numbers) (Sun 1955).

These publications thus served as valuable references for Chinese clinicians and practitioners in the field of tuberculosis treatment, and serve as valuable markers for our own analysis. During this period from the 1940s through the 1950s, Chinese scholars paid attention to Western clinical trial literature and translated articles and disseminated trial results within China. However, while notes regarding trial methodologies were occasionally made (especially, it should be noted, by Delong Su), attention appears to have focused less on methods for reducing biases than on the apparent implications of the (relatively uncritiqued) results of the trials for clinical practice in China.

The Exploratory Phase of Clinical Trials (Late 1940s to Late 1950s)

While some Chinese scholars were translating and disseminating Western trials’ methods and results, others were conducting their own clinical research. In the late 1940s and early 1950s, this research in China primarily consisted of observational studies. In 1948, Wen-chieh Chin and Lanfang Liu from National Shandong University Hospital reported the outcomes of five cases of tuberculous meningitis patients treated with streptomycin (Chin and Liu 1948). Chin and Liu, citing multiple articles in JAMA, mentioned that since the development of streptomycin in 1944, it had been used effectively for the treatment of tuberculosis and tuberculous meningitis (Keefer et al. 1946; Krafchik 1946; Appelbaum and Halkin 1947; Mehas and Truax 1947; Council on Pharmacy and Chemistry 1947; Dosage of streptomycin in tuberculosis 1947)[8]. To this they added their own promising observational findings, further noting that none of the five cases exhibited any observed toxic reactions (Chin and Liu 1948).

In 1950, Muhan Qian[9] reported an observational study of 253 pulmonary tuberculosis patients treated with streptomycin (Qian 1950). The published account did not mention any content related to methodology. Jifa Xu and Songlin Han from Fukang Hospital, Shaoxing, Zhejiang Province also reported an observational study on the effectiveness of streptomycin treatment in 120 cases of pulmonary tuberculosis patients treated between January 1948 and October 1949 (Xu and Han 1950). They aimed ambitiously to determine which types of tuberculosis responded most effectively to streptomycin, the optimal injection frequency, suitable daily dosages, preferred treatment schedules, appropriate timing for alternative therapies, strategies to delay or prevent bacterial resistance, ways to mitigate toxic symptoms, and methods for preventing disease relapse. They did not apparently require a controlled methodology to render their assessments, and felt comfortable reporting that 70% of pulmonary tuberculosis patients experienced significant improvement in symptoms[10]. In 1953, based on observational study results from a total of 205 cases across 16 different institutions, the Chinese Anti-Tuberculosis Association (CATA) highlighted the preliminary efficacy of thioacetazone (Chinese Anti-Tuberculosis Association 1953). However, they also identified shortcomings in the clinical trial methods, such as significant inconsistencies in research protocols among participating institutions, leading to incomplete and limited outcome measures (primarily focused on assessing improvements in radiographic lesions and the presence of side effects). Again, no note was made of the absence of controls in the study.

By the mid-1950s, however, the method of controlled trials gradually emerged in the mainland Chinese academic tuberculosis literature[11]. In 1955, Wentao Jin and Ziying Dai from the Department of General Internal Medicine at Shanghai First Medical College conducted a non-randomized controlled trial of combined isoniazid and streptomycin or isoniazid only for adult tuberculous meningitis treatment. In the methods section of the paper, the authors only mentioned that patients were roughly divided into three groups for treatment (Jin and Dai 1955). They reported preliminary results in the Chinese Journal of Internal Medicine, and stated that due to the limited number of cases (only 35), a relatively short follow-up period, and the absence of definitive treatment protocols, they could provide only an initial report.

Some researchers did begin to emphasize the importance of controlled clinical trials in evaluating tuberculosis treatment effectiveness and to explicitly address methodological issues related to case selection. In 1958, Jueren Zhang (Zhang 1958) from the Beijing Sanatorium for Oriental and African Students (Chinese as “亚非学生疗养院”) pointed out:

To draw objective scientific conclusions, we must thoroughly study and investigate the methodology of clinical research. It is essential to pre-establish clinical research plans for chemotherapy, clearly defining the primary objectives and priorities of the study. Special attention must be paid to the selection of cases. A control group must be established, and in order to compare the therapeutic effects of various drugs when used in combination, it is necessary to establish a standardized combination method as the basis and comparative control standard. Various trial methods must be standardized and uniformly defined, and the evaluation of chemotherapy’s effectiveness must adhere to scientific and reliable uniform standards.

Zhang also emphasized that case selection should be “arbitrary,”[12] unbiased, and grouped. Each group should consist of a sufficient or reasonably large number of patients to yield reliable results. Sometimes, it may require the collaboration of multiple centers (Zhang 1958). Soon, researchers began to take up this challenge.

Large-Scale Analysis and the Start of Randomized Controlled Trials (1960s)

In the early 1960s, a substantial body of case-control tuberculosis studies emerged. Examples included investigations into the impact of drug resistance on pulmonary resection therapy (Fu, Li, and Chen 1963) and an analysis of the factors influencing the outcomes of chemotherapy in 441 non-hospitalized pulmonary tuberculosis patients (Li and Xiao 1963). In 1963, Xueshou Xu and colleagues at the Department of Pulmonary Medicine, Anhui Medical University Affiliated Hospital, conducted a retrospective study involving 1000 cases of pulmonary tuberculosis, particularly examining the effectiveness of tuberculosis drug treatment under different conditions of work and rest for non-hospitalized patients (Xu et al. 1963). The clinical results ultimately suggested that if patients could rest, isoniazid alone was sufficient. However, if they needed to continue working, combination therapy was preferable. Xu and colleagues did not provide any methodological discussion in the document, and the results were solely presented as percentages.

Some scholars questioned Xu and colleagues’ research methodology, exhibiting developing concerns regarding methodological rigor. Chengzhi Xiao (Xiao 1965) argued that while the study used comparative analysis to determine the relative differences in effectiveness between groups, the groups lacked comparability in terms of the complex factors potentially impacting the patients. He also pointed to methodological flaws in the statistics, inconsistencies in the data, and discrepancies between the conclusions and the results of statistical analysis. Xiao mentioned:

In the document, the rates of improvement and deterioration used as efficacy assessment were relative indicators, and the comparison of relative indicators required a scientific determination. Relying on common sense or superficial numerical appearances often leads to errors. Authors may consider as differences some variations that might have been caused by chance, especially when they lack statistical significance (Xiao 1965).

Zhichun Wang (Wang 1965) from Jia Xing Sanatorium likewise expressed doubts about the statistical methods used by the authors, finding that the results did not substantiate the conclusions made by Xu et al. As Wang asserted:

In fact, when assessing the relationship between efficacy and drug types, one should also consider whether factors such as lesion severity were evenly distributed in various drug categories, and these factors were not standardized in the text (Wang 1965).

But 1963 also represented the publication year of the first RCT of tuberculosis treatment in mainland China that we have identified. Since the development of effective tuberculosis drugs, particularly the application of isoniazid, there had been a revolutionary change in the treatment of tuberculosis. The three most commonly used treatment regimens were isoniazid only, isoniazid combined with streptomycin, and isoniazid combined with para-aminosalicyclic acid. To clarify the efficacy of these three commonly used treatment regimens and to assess the impact of different disease conditions on their effectiveness, Shi Wang and colleagues (Wang et al. 1963) from the First Tuberculosis Hospital of Shanghai conducted a relatively large randomized controlled trial. The report outlined the allocation method, whereby a physician who was unaware of the patient’s conditions used randomization. Patients were arranged in order of hospital admission numbers, with every three patients forming a small group. The group assignments were determined according to the sequence of Fisher random number tables. The primary outcomes measured changes in sputum bacteria, and cavity resolution and lesion evolution (as seen on x-ray). The total number of participants in the trial was 151, with 135 patients included in the actual analysis (16 patients were excluded, including 11 with primary drug-resistant bacteria, 3 who left the trial against medical advice, and 2 who were determined not to have tuberculosis). The results showed that sputum conversion to negative was optimal when using isoniazid plus SM, followed in order of efficacy by isoniazid plus PAS. In the discussion, the authors noted:

There is much literature on different drug treatment methods, generally believed to be most effective with isoniazid combined with streptomycin, followed by isoniazid combined with PAS, and least effective with isoniazid alone. However, this view is often based on reports of a single treatment group. There are many factors affecting drug efficacy, and it is only through rigorous simultaneous large-scale comparative methods that we can make clear distinctions and draw conclusions. However, such comparative data are relatively scarce, so there are still different opinions among experts (Wang et al. 1963).

Wang and colleagues also discussed the results of randomized controlled trials conducted in other settings, such as the British MRC (Medical Research Council 1955), the Veterans Affairs system in the United States (Phillips 1959), East African/British MRC (East African Hospitals/Medical Research Council 1960), and British MRC/Madras (Tuberculosis Chemotherapy Centre, Madras 1960), and compared them with the results of their own trial. They emphasized that due to differences in drug dosages, duration of treatment, disease conditions, and other factors between Chinese trials and trials in other settings, it was difficult to directly compare the absolute values of treatment efficacy and arrive at definitive conclusions. Nevertheless, based on the issues clarified by existing data, they believed it was sufficient to propose treatment regimens tailored to different situations and disease conditions.

By the mid-1960s, several additional randomized controlled trials for evaluating the efficacy of tuberculosis chemotherapy drugs would be conducted and published in mainland China. Although these trials conducted in Shanghai and Beijing mentioned the use of random allocation, some trials lacked a methods section (Zhang 1966) or divided the participants into two groups without specifying the random allocation process used to compare the two groups’ effectiveness (Shen 1965; Tong et al. 1966). In these early tuberculosis randomized controlled trials, there was also no mention of methods to reduce biases in their reports, and the sample sizes were around 100 cases each. Still, the methods used can at times be inferred from the text of the paper, as when in 1966, Jinyuan Zhang (Zhang 1966) conducted a randomized controlled trial aiming to explore the optimal daily dosage and frequency of PAS administration. Zhang mentioned the method of using the same disease cases, forming pairs, and randomly assigning them to Groups A (PAS+Isoniazid divided into two oral doses daily) and B (PAS+Isoniazid divided into four oral doses daily) based on random sampling numbers. The objective was to achieve better efficacy with fewer side effects. While the British MRC trials emphasized the role of high doses (16g/day-20g/day) (Medical Research Council 1953b), the blood concentration measurements in Zhang’s study indicated that Chinese patients could seemingly achieve the desired results with sodium para-aminosalicylate (PAS-Na) at lower doses to avoid causing more side effects and unnecessary waste. And it demonstrates to us the intention of Chinese researchers to both engage directly with the Western literature and to pursue RCTs of their own by this time, directly on the eve of the Cultural Revolution.

Large-Scale, Multi-Center Randomized Controlled Trials of Short-Course Regimens (from the late 1970s) and the Relationship to Hong Kong

As with controlled clinical trials more generally (Yu, Chen, and Podolsky 2025), tuberculosis trials and publications appear to have been curtailed during the Cultural Revolution. For instance, the Chinese Journal of Antituberculosis, established in 1948, was discontinued in 1966 and resumed publication in 1979 (Huang 1979). The Chinese Journal of Tuberculosis and Respiratory Diseases, founded in 1953, first ceased publication in 1959[13] and resumed publication in September 1978 (Li and Tang 2024). Yet by the late 1970s, we begin to see the advent of large-scale tuberculosis RCTs, often in direct engagement with British MRC trials, including those conducted in Hong Kong.

One of the challenges in the advancement of chemotherapy for tuberculosis was the inability of some tuberculosis patients to adhere to the full course of standardized treatment. Shortening the treatment duration while achieving the same efficacy as standardized treatment thus became a new focus of attention and research. In 1972, the East African/British MRC collaboration first reported on an RCT of short-course chemotherapy, revolutionizing tuberculosis chemotherapy (East African British Medical Research Councils 1972). During the same period, the Hong Kong Government Chest Service had officially begun collaborating with the British MRC, starting in 1967 (Hong Kong Tuberculosis Treatment Services British Medical Research Council 1975) to conduct a series of important tuberculosis-related research projects and randomized controlled trials, including a series of studies of short-course therapy (first started in 1972) and publishing results starting in 1975 (Hong Kong Tuberculosis Treatment Services British Medical Research Council 1975; Hong Kong Chest Service British Medical Research Council 1977; Hong Kong Chest Service British Medical Research Council 1978; Hong Kong Chest Service British Medical Research Council 1979; Hong Kong Chest Service British Medical Research Council 1981; Hong Kong Chest Service British Medical Research Council 1982; Hong Kong Chest Service/British Medical Research Council 1987; Hong Kong Chest Service British Medical Research Council 1991; Hong Kong Chest Service Tuberculosis Research Centre and Madras British Medical Research Council 1991). In this context, China’s National Tuberculosis Prevention and Control Conference in 1978 decided to include short-course chemotherapy for pulmonary tuberculosis as one of its own research topics. Thereafter, the National Coordinating Group of Investigations on Short-course Chemotherapy was established. As requested by the Ministry of Health, the Beijing Tuberculosis Research Institute (now Beijing Chest Hospital) was the leading institute, the Shanghai Tuberculosis Control Institute was the second leading institute, and collaborating with another 23 institutes, including ones in Guangzhou, Guangxi, and Inner Mongolia, they initiated a randomized clinical controlled trial comparing the efficacy of two short-course regimens (6 months and 9 months) with standardized treatment in 566 cases. In 1982, the results from the first year and a half of the trial were published (National Coordinating Group of Investigations on Short-course Chemotherapy 1982), though the published results did not provide detailed explanations of the randomization methods or how biases were reduced. This study cited the 1975 RCT conducted by Hong Kong/British MRC, and cited it in the determination of the primary endpoints – smear examination.[14]

With the initial collaborative research results suggesting that a shortened treatment regimen could achieve the same efficacy as the 1.5-year standardized treatment, the National Coordinating Group of Investigations on Short-course Chemotherapy conducted a second clinical trial, published in 1984 (National Coordinating Group of Investigations on Short-course Chemotherapy 1984). In the methods section, clear selection criteria were established, and randomization was conducted to assign participants to four groups. A total of 1029 participants completed the trial. The results of the second trial, with intermittent dosing after intensified treatment, were generally consistent with the results of an 8-month short-course regimen reported in Hong Kong in 1978 (Hong Kong Chest Service/British Medical Research Council 1978).

Starting from the early 1980s, as attention to RCTs in mainland China began to expand more generally (Yu, Chen, and Podolsky 2025), Chinese researchers began to publish specifically on the methodology of tuberculosis clinical trials, especially the methods of randomized controlled trials. In 1980, Guanqing Kan, the director of the Beijing Tuberculosis Prevention and Control Institute, published an article in the Chinese Journal of Antituberculosis, discussing the scientific aspects of chemotherapy in tuberculosis. As Kan stated:

On the one hand, we must respect science; anything with sufficient objective scientific basis should be believed and accepted. On the other hand, when there isn’t enough scientific basis, we should not blindly proceed. We have taken the wrong path on this issue. Some researchers often work based on subjective wishes, enthusiasm, and imagination, without considering or giving little thought to its scientific foundation. Some researchers, due to traditional habits, were reluctant to believe and accept new things with sufficient scientific basis. Both of these show significant obstacles to the modernization of tuberculosis prevention and control efforts and the full utilization of chemotherapy (Kan 1980).

That same year, Kan translated the chapter written by Czech tuberculosis expert Kurt Toman, originally titled “What are the principles and requirements of a controlled chemotherapy trial?” and published by the World Health Organization in 1979. Kan translated this chapter word by word in the Chinese Journal of Antituberculosis (Kan 1980). As Toman had proposed in 1979:

It is mainly in the last 25 years that determined efforts have been made to use scientific techniques in evaluating the treatment of tuberculosis on a larger scale. An important advance in this field has been the development of an assessment method known as the controlled trial, which has been found particularly suitable for studying the effect of chemotherapeutic substances. Since their introduction, many controlled trials have been carried out, and have made it possible to establish the efficacy, toxicity, and applicability of practically all the chemotherapeutic regimens currently used. However, there are still physicians who do not appreciate the value and scope of the method. And there are some authors who call their investigations controlled trials without observing the essential requirement (Toman 1979).

Meanwhile, researchers in mainland China appear to have continued to recognize the role of Hong Kong’s scientific research in the field of tuberculosis chemotherapy, and to have appreciated the rigor of their studies (Hong Kong Tuberculosis and Chest Service 2024). In 1985, the aforementioned Guanqing Kan, still the director of the Beijing Tuberculosis Prevention and Control Institute, was invited to visit Hong Kong by the Hong Kong Tuberculosis, Heart, and Chest Diseases Association. During his visit, while observing tuberculosis prevention efforts in Hong Kong, he noted that Hong Kong’s scientific research work was highly respected and that it had made significant contributions on the international stage. Kan remarked that Hong Kong’s scientific research was conducted rigorously and meticulously, adhering strictly to the scientific method. He also noted that in their selection of cases for chemotherapy research, they adhered strictly to pre-allocated randomization (prepared in advance by the London MRC) with sealed and sequenced patient assignments (Kan 1986).

Continuing such an invocation of the relevance of the Hong Kong/British MRC history for mainland China, in 1991, the Chinese Journal of Antituberculosis published the translation of an article written by Zhaolin Chen, the director of the Department of Chest Medicine at the Government Health Service of Hong Kong, titled “The Role of Scientific Research in Tuberculosis Chemotherapy in Hong Kong” (Chen, Guo, and Jin 1991). This translated article noted that prior to the early 1960s, Hong Kong had also faced challenges such as high treatment failure rates and drug resistance. Therefore, the Hong Kong government had invited Frederick Heaf and Wallace Fox from the UK to report on tuberculosis prevention and control measures in Hong Kong, and to provide recommendations for future development. This had made the Hong Kong government fully aware of the importance of clinical research in tuberculosis and had led to practice-changing collaborative clinical trials. The editors of the Chinese Journal of Antituberculosis also pointed out:

The research in the field of tuberculosis in Hong Kong was highly recognized in the academic community. Their research was based on local needs, with clear objectives and results that not only guided practice but were also widely applicable to real work situations. This research design and approach had a significant influence on China’s tuberculosis workers (Chen, Guo, and Jin 1991).

In 1996, Shaohong Lee, the President of the Hong Kong Tuberculosis, Heart and Chest Diseases Association, published an article in the Chinese Journal of Antituberculosis, aiming to summarize the development of tuberculosis prevention and control in Hong Kong and promote collaboration between mainland China and Hong Kong in tuberculosis prevention and control (Li 1996). The article emphasized that over the past fifty years (1950s-1990s), tuberculosis prevention and control in Hong Kong had achieved significant success, with research on tuberculosis drug treatment conducted in collaboration with the British MRC playing a crucial role. By this time, as we have seen, RCTs had become more broadly implemented within mainland Chinese medicine.

Tuberculosis-related RCTs may have been dwarfed by the more general advent of RCTs by this time (Yu, Chen, and Podolsky 2025), but they appear to have played a pioneering role in generating attention to such methodology. And they provide a useful window into the relationship between China and the West in the evaluation of therapeutic efficacy and the uptake of the RCT in particular.

Traditional Chinese Medicine in Tuberculosis Treatment

To this point, it appears that the advent of RCTs for traditional Chinese medicine (TCM) of tuberculosis in mainland China lagged behind their western chemotherapeutic counterparts [15] That said, TCM has a history of over a thousand years in treating tuberculosis. Among the various TCM methods for treating pulmonary tuberculosis, the use of “Bai Ji” has been documented in mainland Chinese literature since the 1950s (Jinzhou Zijing Mountain Tuberculosis Hospital 1958). In 1959, Ben Zhang provided a review of the past decade’s research on TCM and traditional Chinese herbs in tuberculosis in the Chinese Journal of Antituberculosis. Zhang mentioned that many clinical studies were conducted during the previous decade, primarily observational studies (Zhang 1959). Nevertheless, Zhang did mention that seven tuberculosis inpatient institutions in Beijing jointly observed the results of acupuncture combined with tuberculosis drugs in 154 cases of “infiltrative” [16]pulmonary tuberculosis patients for a duration of 3 months. Simultaneously, another 154 cases using only tuberculosis drugs were set up for comparative observation. The conditions of the two groups were roughly similar, with the former showing higher efficacy than the latter.[17]

From there, controlled trial methodology did begin to appear in TCM tuberculosis studies. In 1975 (notably, amidst the Cultural Revolution), the Department of Infectious Diseases of the 51^st Hospital of the People’s Liberation Army reported on a controlled study on the use of Bai Ji in treating pulmonary tuberculosis, conducted from 1972 to 1974. The study had three groups: Group A received only Bai Ji, Group B received Bai Ji plus isoniazid, and Group C received isoniazid, PAS-Na, and streptomycin. The results were published in the New Medicine journal and showed that the use of Bai Ji appeared to have superior efficacy in terms of lesion absorption, cavity closure, and sputum conversion compared to the exclusive use of Western medicine. Moreover, there was no significant difference when Bai Ji was combined with Western medicine. The article presented the three groups without specifying the grouping methods. However, in the discussion, the study acknowledged that due to the lack of randomization, unbiased significance testing could not be performed (51st Hospital of the Chinese People’s Liberation Army 1975).

Since the 1990s, by which point RCTs were being conducted more generally in mainland China, there have been several randomized, controlled trials employing integrated traditional Chinese and Western medicine in the treatment of tuberculosis (Zhang et al. 1992; Wei et al. 1995). More generally with respect to TCM, with the dissemination and advancement of evidence-based medicine in China, RCTs of TCM have been widely promoted to test their therapeutic effects. Simultaneously, the Chinese government has formulated a series of policies applicable to the development of TCM. For instance, in certain situations, Chinese classical formulas for pharmaceutical prescriptions may be exempted from clinical trials and still remain eligible for approval (National Medical Products Administration 2018; Luo et al. 2021). However, the implementation of this policy has generated diverse opinions and criticism, with some expressing concerns that the lack of clinical trials may impact the assessment of the safety and efficacy of these medicinal formulas (Traditional Chinese medicine needs proper scrutiny 2017).

Conclusion

Tuberculosis has long served at the leading edge of attempts to judge therapeutic efficacy, especially, in the post-World War II era, through the randomized controlled trial. Much as it served as a focus of such studies in the United States and Great Britain, tuberculosis appears to have served as a focus of such early efforts in mainland China. Yet the history of clinical trials for the treatment of tuberculosis also serves as a window into the evolution of trial methodology more generally in mainland China, into China’s engagement with Western medicine (and Western medical literature), and into the dynamic between Western and Traditional Chinese Medicine. We hope, through our examination of the existing clinical literature, to have made a useful start for this important and revealing sub-category of the history of clinical trials in China. And we recognize that this history opens up many sites for further inquiry and contextualization.

Acknowledgments
The authors would like to express their deepest gratitude to Iain Chalmers, Jinling Tang, Ted Kaptchuk, Qi Tan, Ming Liu, Mike Clarke, and Karen Robinson for their insights and feedback on the manuscript.

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Footnotes:

[1] Journals reviewed include the National Medical Journal of China, Journal of Internal Medicine (now Chinese Journal of Internal Medicine), Chinese Journal of Tuberculosis (now Chinese Journal of Tuberculosis and Respiratory Diseases), and Chinese Journal of Antituberculosis. Through manual searching of journals, all clinical trials related to tuberculosis treatment published before 1980 were reviewed.

[2] Because Guo’s affiliation in the document was abbreviated as ‘河大医学院’ (He Da Medical School), we only know it was a medical school, but we are not sure which specific medical school and where it was.

[3] For the resistance to including a control group receiving no medication in the VA collaborative study, see: (Marks 1997, pp. 116-120).

[4] The document did not specify the authors’ affiliation.

[5] The document did not specify who translated it.

[6] It is unclear to which article in particular Guanqing Kan was referring.

[7] The document did not specify the author’s affiliation.

[8] It appears that compared to the studies published in BMJ, Chinese scholars tended to reference more articles published in JAMA or the American Review of Tuberculosis. This merits further investigation.

[9] The document did not specify the author’s affiliation and the institution where this trial was conducted.

[10] ‘Significant improvement in symptoms’ in Chinese as “有显著的症状好转” p.13.

[11] From the 1950s, the number of clinical studies related to tuberculosis in China gradually increased. Ling He (He 2012) in 2012 analyzed 170 articles related to tuberculosis published in the Chinese Journal of Tuberculosis and Respiratory Diseases from 1953 to 1958. She found a number of clinical articles, yet did not provide any enumeration of controlled trials of the treatment of tuberculosis. It is relevant that He mentioned in the thesis that Shaoqing Wu (Wu 1947), in the English edition of the Chinese Medical Journal in 1947, discussed that Denmark, the United States, Canada, and other countries had proven through a series of controlled trials that BCG vaccine could indeed prevent tuberculosis. This BCG thread would seem to warrant additional study in its own right.

[12] The term “random” is typically translated Chinese as “随机” in clinical trials. However, the word used by the original author is “arbitrary (Chinese as 任意).” Upon careful reading of the original text, it is believed that the author may have intended to convey the meaning of “random”.

[13] From 1959 to 1966, the journal experienced several interruptions. There are currently no articles included on the journal’s website between 1960 and 1978. 

[14] Of note, the 1975 RCT was reference 3 of the original article. Within the main text of the article, citations were made to (2,4), rather than (2-4), but this was in a section which clearly seemed to be referencing citation 3 along with citations 2 and 4. It thus appears that (2-4) was meant here. Regardless, the 1975 RCT conducted by Hong Kong/British MRC was clearly referenced by the mainland China investigators.

[15] A meta-analysis of the clinical evaluation of traditional Chinese medicine in the treatment of tuberculosis (Guo et al. 2022), published in 2022, systematically searched and screened relevant studies (up to January 30, 2022). After excluding studies with incomplete, duplicated, or erroneous data, as well as those lacking sufficient diagnostic and efficacy evaluation indicators, a total of 10 randomized controlled trials (RCTs) were included, with the earliest RCT published in 2014 (Feng et al. 2014; Xi et al. 2014).

[16] “Infiltrative” in Chinese as “浸润型”.

[17] The reference mentions that this information is from a conference paper abstract, and relevant abstracts for this conference cannot be currently retrieved. However, in 1959, the Chinese Journal of Antituberculosis published an article summarizing the conference and also mentioned this study. The article did not specify whether it was a randomized controlled trial; it only mentioned the presence of a control group and that the results in the study group were better than in the control group (Ge and Dong 1959).