History of clinical trials for the treatment of tuberculosis in China. Part 1: early ‘translational’ work and observational and non-randomised studies

Abstract

The general history of the randomised 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.¹ Starting from the 1990s, large-scale multicentre 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 20th century.^2
–4 For instance, the 1948 British Medical Research Council (MRC) assessment of streptomycin (SM) for tuberculosis was recognised 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.^4,5 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.⁶ And tuberculosis treatment articles and trials, from the late 1940s onwards, 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 onwards,¹ 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. In Part 1, we relate the early history of this research and literature, focused on translations of Western studies, and on observational trials and non-RCTs in mainland China. In Part 2, we will examine the advent of RCTs for the evaluation of tuberculosis, in mainland China and in Hong Kong, and concerning Western pharmaceuticals and TCM alike.

Table 1.

Key events of clinical trials for the treatment of tuberculosis in China.

Time	Key events
Late 1940s and early 1950s	Translated and disseminated the results of non-randomised clinical trials for tuberculosis treatment from Western countries
Late 1940s	Synthesised overseas clinical research results and began to conduct observational studies
Early 1950s	Started to summarise and disseminate British MRC RCTs’ results related to isoniazid
Mid-1950s	Conducted non-RCTs
1963	Published the first RCT of tuberculosis treatment related to the efficacy of isoniazid, isoniazid combined with SM, and isoniazid combined with PAS
1967	The Hong Kong Government Chest Service officially began collaborating with the British MRC
1975	The first Hong Kong Tuberculosis Treatment Services/British MRC controlled trial was published
Late 1970s	Large-scale and multi-centre studies in mainland China were conducted and published
1990s onwards	RCTs employing integrated traditional Chinese and Western medicine in the treatment of tuberculosis have emerged

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 summarised by Chinese scholars in reputable journals.^a

For example, from the late 1940s and early 1950s onwards, Chinese scholars began translating and publishing relevant material from Western publications on SM 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’,⁷ was translated by Conghou Guo^b and published in 1948 in the National Medical Journal of China.⁸ 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 SM in tuberculosis.⁹ While the VA study was not a ‘controlled’ study per se, it entailed some comparative components relating to differing doses of SM employed among the 2780 patients to that point.^c Yet, in the article’s translation by Yannan Zhu et al.^d in 1950 in the National Medical Journal of China,¹⁰ 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’¹¹ (in which the classic 1948 British MRC SM trial was not cited) was translated and published in 1950 in the Chinese Journal of Internal Medicine.^12,e

In addition to straightforward translations of foreign-language literature, Chinese scholars in the late 1940s and early 1950s began to synthesise overseas clinical research results, with some references made to controlled trials. In 1949, Yang and Zhang¹³ 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. 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 with equivalent control cases (‘motsvarande kontrollfall’; it was unstated precisely how that control group was formulated).¹⁴ Similarly, in 1951, Guanqing Kan¹⁵ from the Beijing Municipal Public Health Bureau reported on the preliminary results of a controlled clinical trial on SM therapy for pulmonary tuberculosis, as presented in January 1951 at the 10th Streptomycin Committee Meeting in the United States.^f

Of note, we have found no translated or summarised versions of the British MRC’s 1948 RCT of SM 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 et al.¹) 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 RCT of isoniazid treatment for pulmonary tuberculosis (published in the BMJ in 1952)¹⁶ in the National Medical Journal of China¹⁷ and Chinese Journal of Internal Medicine, respectively.¹⁸ 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 with Su, Mao did not provide a description of the randomised, 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.¹⁹ 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 categorisation of applicable cases into three lesion types, and the dosages for the three treatment groups.²⁰ The British MRC’s original publication itself outlined their randomisation 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 SM versus with PAS in the treatment of pulmonary tuberculosis.²¹ Xianming Sun^g 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 randomisation 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).²²

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 SM.²³ Chin and Liu, citing multiple articles in JAMA, mentioned that since the development of SM in 1944, it had been used effectively for the treatment of tuberculosis and tuberculous meningitis.^24
–29^,h To this they added their own promising observational findings, further noting that none of the five cases exhibited any observed toxic reactions.²³

In 1950, Muhan Qian^30,i reported an observational study of 253 pulmonary tuberculosis patients treated with SM. 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 SM treatment in 120 cases of pulmonary tuberculosis patients treated between January 1948 and October 1949.³¹ They aimed ambitiously to determine which types of tuberculosis responded most effectively to SM, 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.^j In 1953, based on observational study results from a total of 205 cases across 16 different institutions, the Chinese Anti-Tuberculosis Association highlighted the preliminary efficacy of thioacetazone.³² 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.^k In 1955, Wentao Jin and Ziying Dai from the Department of General Internal Medicine at Shanghai First Medical College conducted a non-RCT of combined isoniazid and SM 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.³³ 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 emphasise the importance of controlled clinical trials in evaluating tuberculosis treatment effectiveness and to explicitly address methodological issues related to case selection. In 1958, Jueren Zhang³⁴ 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 emphasised that case selection should be ‘arbitrary’,^l 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 centres.³⁴ Soon, as will be discussed in Part 2, researchers began to take up this challenge.

Footnotes

Declarations

Notes

References

Chen

Podolsky

2025. The History of Controlled Clinical Trials in China. JLL Bulletin: Commentaries on the history of treatment evaluation. See www.jameslindlibrary.org/articles/the-history-of-controlled-clinical-trials-in-china/ (last checked 7 May 2025).

Marks

HM.

The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900–1990. Cambridge: Cambridge University Press, 1997.

Gabriel

JM.

The testing of sanocrysin: science, profit, and innovation in clinical trial design. J History Med Allied Sci 2014; 69: 604–632.

Chalmers

Statistical theory was not the reason that randomisation was used in the British Medical Research Council’s clinical trial of streptomycin for pulmonary tuberculosis. In: Jorland

Opinel

Weisz

, eds. Body Counts: Medical Quantification in Historical and Sociological Perspectives. Montreal: McGill-Queens University Press, 2005: 309–334.

Medical Research Council. Streptomycin treatment of pulmonary tuberculosis. BMJ 1948; 2: 769–782.

Fox

Ellard

Mitchison

DA.

Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946–1986, with relevant subsequent publications. The International Journal of Tuberculosis and Lung Disease 1999; 3: S231–S279.

Hinshaw

Feldman

Pfuetze

. Treatment of tuberculosis with streptomycin: a summary of observations on one hundred cases. JAMA 1946; 132: 778–782.

Guo

Treatment of tuberculosis with streptomycin: a summary of observations on one hundred cases. Natl Med J China 1948; 34: 241–246. [郭从厚 (1948). 用链霉素治疗结核病(一百病例之初步分析). 中华医学杂志 34: 241–246.]

Council on Pharmacy and Chemistry. Streptomycin in the treatment of tuberculosis: current status. JAMA 1948; 138: 584–593.

10.

Zhu

Zhang

Tang

Streptomycin in the treatment of tuberculosis. Natl Med J China 1950; 36: 51–53. [朱燕南,张佩瑛,唐锦治, (1950). 结核病之链霉素治疗. 中华医学杂志 36: 51–53.]

11.

Pfuetze

Pyle

MM.

Streptomycin in the treatment of tuberculosis. JAMA 1949; 139: 634–639.

12.

Streptomycin in the Treatment of Tuberculosis. Chin J Int Med 1950; 2: 231–233. [链霉素对于结核病的治疗 (1950). 中华内科杂志 2: 231–233.]

13.

Yang

Zhang

Chemotherapy of tuberculosis: I. p-aminosalicylic acid (PAS). Natl Med J China 1949; 35: 109–122. [杨藻宸,张昌绍 (1949). 结核病之化学治疗: I. 对氨柳酸P-Aminosalicylic Acid (PAS). 中华医学杂志 35: 109–122.]

14.

Alin

Difs

Clinical experience with p-aminosalicylic acid (PAS) in pulmonary tuberculosis. Nordisk Med 1947; 33: 151–158.

15.

Kan

Preliminary report on the clinical trial of streptomycin in the treatment of pulmonary tuberculosis. Chin J Antitubercul 1951; Z2: 6. [阚冠卿 (1951). 抗链霉素肺结核病药物治疗临床试验初步报告. 防痨通讯 Z2: 6.]

16.

Medical Research Council. The treatment of pulmonary tuberculosis with isoniazid. Br Med J 1952; 2: 735–746.

17.

Introduction to the clinical trial report on isoniazid for the treatment of pulmonary tuberculosis. Natl Med J China 1953; 39: 214–216. [苏德隆 (1953). 异烟硷醯肼治疗肺结核临床试验报告介绍. 中华医学杂志 39: 214–216.]

18.

Mao

Isoniazid treatment for pulmonary tuberculosis. Chin J Int Med 1953; 1: 227. [毛应骥 (1953). 异菸醯肼治疗肺结核. 中华内科杂志 1: 227.]

19.

Medical Research Council. Isoniazid in the treatment of pulmonary tuberculosis. Second Report. Br Med J 1953; 1: 521–536.

20.

Zhang

Isoniazid treatment for tuberculosis. Chin J Tubercul Respir Dis 1953; 1: 145–149. [张锦垣 (1953). 肺结核的异烟肼治疗. 中华结核病科杂志 1: 145–149.]

21.

Medical Research Council. Isoniazid in combination with streptomycin or with PAS in the treatment of pulmonary tuberculosis. Br Med J 1953; 2: 1005–1014.

22.

Sun

Comparison of the efficacy of isoniazid combined with streptomycin or PAS in the treatment of tuberculosis. Chin J Int Med 1955; 3: 78–80. [孙显明 (1955). 异菸肼与链霉素或对氨柳酸并用治疗肺结核效果的比较. 中华内科杂志 3: 78–80.]

23.

Chin

Liu

Streptomycin treatment of tuberculous meningitis. Natl Med J China 1948; 34: 233–239. [秦文杰, 刘兰芳 (1948). 链霉素治疗结核性脑膜炎. 中华医学杂志 34: 233–239.]

24.

Keefer

Blake

Lockwood

Long

Marshall

Jr and Wood

Jr.

Streptomycin in the treatment of infections: a report of one thousand cases. JAMA 1946; 132: 4–11.

25.

Krafchik

LL.

Tuberculous meningitis treated with streptomycin. JAMA 1946; 132: 375–376.

26.

Appelbaum

Halkin

Tuberculous meningitis and miliary tuberculosis arrested with streptomycin. JAMA 1947; 135: 153–155.

27.

Mehas

Truax

WE.

Streptomycin in tuberculous meningitis. JAMA 1947; 135: 155–157.

28.

Council on Pharmacy and Chemistry. Streptomycin. JAMA 1947; 135: 839.

29.

Dosage of streptomycin in tuberculosis (1947). JAMA 135: 842.

30.

Qian

Streptomycin treatment for tuberculosis. Natl Med J China 1950; 36: 3–10. [钱慕韩 (1950). 肺结核之链霉素治疗. 中华医学杂志 36: 3–10.]

31.

Han

Analysis of one hundred and twenty cases of tuberculosis treated with streptomycin. Natl Med J China 1950; 36: 11–14. [徐纪法,韩颂霖 (1950). 用链霉素治疗肺结核一百廿病例之分析. 中华医学杂志 36: 11–14.]

32.

Chinese Anti-Tuberculosis Association. Summary of clinical trials on thioacetazone (preliminary report). Chin Pharm J 1953; 9: 371–372. [中国防痨协会 (1953). 氨硫脲床試驗總結(初步报告). 中国药学杂志 09: 371–372.]

33.

Jin

Dai

Preliminary report on the combined therapy of isoniazid and streptomycin for adult tuberculous meningitis. Chin J Int Med 1955; 3: 844–849. [金问涛,戴自英 (1955). 成人结核性脑膜炎的异菸肼、链霉素联合疗法初步报告. 中华内科杂志 3: 844–849.]

34.

Zhang

Several issues in the chemotherapy of pulmonary tuberculosis. Chin J Antitubercul 1958; 3: 27–30. [张觉人 (1958). 关于肺结核化学疗法中的几个问题. 中国防痨 3: 27–30]

35.

The Introduction into China of Western Medicine: A Case Study in Tuberculosis (1900–1967). Shanghai: Shanghai Jiao Tong University, 2012. [何玲 (2012). 西医传入中国：结核病案例研究(1900–1967). 上海交通大学.]

36.

BCG vaccination for tuberculosis control in China. Chin Med J 1947; 65: 381–383.