Abstract

The advent of randomized controlled trials (RCTs) in mainland China remains largely unexplored. We offer here what we hope is a useful starting-point. We begin with a brief account concerning the pre-RCT era, and then trace the scattered RCTs in the 1960s that were followed by more robust expansion from the late 1970s (after the Cultural Revolution) onward. We then turn to the large-scale multicenter RCTs that, starting from the early 1990s, began to be conducted and published. With the development of clinical epidemiology and evidence-based medicine in China, the number and quality of RCTs have been improved. Yet we find an enduring tension between aspirations to conduct clinical trials, and self-critique concerning the current standards of trial ethics and methodological rigor. Such tension persists to the present day. We have grounded this paper in extensive searching of the Chinese medical literature, and provide documentation of the specifics of our search strategies. Through this approach, we hope to have set a base for continued efforts to further advance and contextualize this history.

Introduction

From the mid-20th century, randomized controlled trials (RCTs) rose to become the gold standard for evaluating therapeutic efficacy throughout much of the world, despite occasional criticism (Marks 1997; Bothwell et al. 2016). Especially towards the end of the 20th century, the development of “evidence-based medicine” elevated RCTs to the top of the evidence hierarchy (Cook et al. 1992; Daly 2005). Initially prevalent in Western countries such as the United Kingdom and the United States, RCTs gradually extended their influence into diverse domains, encompassing social sciences, economics, technology, and policy interventions (Bothwell et al. 2020). The methodology of RCTs did not materialize overnight but evolved over time, incorporating elements such as control groups (including through alternate allocation, prior to the advent of randomization), methods to mitigate multiple forms of bias, statistical innovations to enable the demonstration of efficacy, and considerations of ethics (Bothwell et al. 2020; Chalmers et al. 2012).

Over the past 75 years, the principles and methods of RCTs have been disseminated worldwide. However, the circumstances concerning how and when RCTs were initially conducted and disseminated in mainland China, as well as their impact on clinical decision-making, remain largely unexplored. Examining this in detail – amidst such contexts as China’s unique political, social, and cultural history throughout the 20^th century, the complicated and evolving relationship between China and the West (including the former British colony of Hong Kong), the complicated relationship between Traditional Chinese Medicine (TCM) and Western medicine over the course of the 20^th century, and the development of China’s own pharmaceutical industries, hospitals, medical journals, and medical schools – would represent a field of study in itself. We thus offer here what we hope is a useful starting-point.

More recent reviews related to the advent and history of clinical trials in mainland China – often grounded in extensive empirical work – have been extraordinarily valuable to our own work here (Tang, Zhan, and Ernst 1999; Tian et al. 2021; Li et al. 2021; Li et al. 2008)^[1]. Building on this, an examination of the existing historiography, combined with newly available (and extensive) full-text searching of Chinese medical journals, affords an overview of the advent of clinical trials and research ethics in China.

We begin with a brief account concerning the pre-RCT era, and then trace the scattered RCTs in the 1960s that were followed by more robust expansion from the late 1970s (after the Cultural Revolution) onward. We then turn to the large-scale multicenter RCTs that, starting from the early 1990s, began to be conducted and published in mainland China. With the development of clinical epidemiology and evidence-based medicine in China, the number and quality of RCTs have been improved. Yet we find an enduring tension between aspirations to conduct clinical trials, and self-critique concerning the current standards of trial ethics and methodological rigor. Such tension persists to the present day.

Clinical Trials in China Prior to the Advent of RCTs

Existing historiography points to scattered pre-1949 attempts at clinical trials in China. Most famously, in the 11th century (Song Dynasty in 1061), the Atlas of Materia Medica (Ben Cao Tu Jing), the earliest documented Chinese government-organized pharmacopeia, documented a controlled trial to evaluate the efficacy of ginseng (Senior 2009). It was mentioned that in order to evaluate the effect of genuine Shangdang ginseng, two individuals were asked to run together. One was given ginseng, while the other ran without it. After running for approximately three to five li (equivalent to 1500 to 2500 meters), the one without the ginseng developed severe shortness of breath, while the one who took the ginseng breathed evenly and smoothly. It is not known where the idea of a controlled experiment using individuals originated in Ancient China, but it may have reached China through the Silk Road from Persia (Gluud and Wang 2002).

In the early 20th century, amidst larger efforts to reduce plague mortality in Hong Kong, as well as tensions between TCM and Western medicine, Henry Blake, the Governor of Hong Kong from 1898-1904, made a rough comparison of patients with plague receiving TCM with others receiving Western medicine. During a defined period of observation, 25 patients were treated with TCM, with 21 deaths. This was deemed largely equivalent to cases of “Chinese” patients treated during the same time period (with careful attention given to making such a comparison across the same time period, in an attempt to render the groups comparable) at a western hospital established in Hong Kong, with an 86.2% mortality rate. Although Blake was aware that the numbers in the trial were too small to afford a sound basis for scientific comparison, he considered it noteworthy that there was a miniscule difference in mortality rate between the two realms of treatment (Lei 2014; Blake 1904)^[2].

The Advent of RCTs in Mainland China (1950s- 1960s)

In the sparse existing historiography, there is still no consensus regarding when an RCT was first developed and published in China. Some researchers have stated that controlled trials involving TCM were reported in the late 1950s or early 1960s, though specific articles were not cited by them (Xie and Li 1995). Others have noted (again, without directly citing the relevant articles) that the first Western medicine RCT developed and published in China was attributed to Delong Su (likely related to schistosomiasis or what was then considered “paracholera”^[3]) in the early 1960s (History of Clinical Trials in China 2002; Ding, Wei, and He 2003; Liu 2002; Liu 2001). We have not yet found a published RCT to support this claim^[4], though Delong Su would clearly be regarded as one of the pioneers in clinical epidemiology in China (Ding, Wang, and Zhao 2021), and in 1962 published on the concepts, methods, and significance of RCTs in an article titled “Clinical Trial Design (临床实验设计)” in the National Medical Journal of China (Su 1962)^[5].

Xuezhang Zhou and colleagues from the Jiaxing Institute for the Prevention and Treatment of Schistosomiasis, however, do appear to have conducted several clinical trials with components of randomization concerning the treatment of schistosomiasis during this period. During the summer and fall of both 1962 and 1963, they divided 66 patients with moderate to severe acute schistosomiasis into one of two groups through a “random sampling method.”^[6]  The patients were treated with the anti-parasitic furapromidium versus a combination of an adrenocortical hormone (prednisone) and antimony potassium tartrate^[7]. The trial result was published in abstract form in 1965 in the Chinese Journal of Internal Medicine (Zhou, Huangfu, and Zhou et al. 1965). In parallel, between 1961 and 1963, Zhou and colleagues conducted a controlled trial involving 250 cases of children with acute schistosomiasis. To compare the efficacy of furapromidium with that of prednisone combined with antimony potassium tartrate, 200 cases were treated with furapromidium alone, while another 50 cases were randomly divided into two groups. One group received furapromidium (25 cases), and the other group received prednisone combined with antimony potassium tartrate (25 cases). The results, published in 1965 in the National Medical Journal of China, demonstrated that furapromidium had a significantly greater antipyretic effect than prednisone combined with antimony potassium tartrate (Zhou, Huangfu, and Wei et al. 1965).

At the same time, tuberculosis researchers, often engaged with western literature (e.g., from the United States and Great Britain), served to pioneer the use of RCTs in mainland China (Yu, Chen, and Podolsky 2025). In 1963, Shi Wang and colleagues (Wang et al. 1963) from the First Tuberculosis Hospital of Shanghai published a relatively large RCT to clarify the efficacy of three commonly used treatment regimens (isoniazid only, isoniazid combined with streptomycin (SM), and isoniazid combined with para-aminosalicylic acid (PAS)). Their report outlined their allocation method, whereby a physician 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 then 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.

Single-Center or Small-Sample RCTs (Post-Cultural Revolution to the mid-1990s)

During the Cultural Revolution (1966-1976), we find a gap concerning RCTs, in an era in which many medical research institutions stopped scientific activities or were disbanded (Tian et al. 2010). Most clinical trials were forcibly terminated (Liu 2002), and medical journals suffered severe devastation (with the number of officially published journals decreasing from 790 in 1965 to 20 in 1969) (Yin 2012).  Thereafter, the late 1970s and early 1980s appear as a critical inflection point for the increasing recognition in China of the utility of RCTs. At the end of 1979, Kerr White, who as Deputy Director for Health Sciences at the Rockefeller Foundation initiated the International Clinical Epidemiology Network (INCLEN), wrote to the Chinese Ministry of Health, inviting Delong Su to give a two-week international clinical epidemiology workshop at the University of Cambridge in the United Kingdom in September 1980 (Wang et al. 1987; Luo 1991). Moreover, three senior clinical medicine professors from China were invited to participate and enhance their knowledge. One of the participating professors, Decheng Luo from the West China University of Medical Sciences, reported that he “deeply recognized that if every clinician involved in research could grasp clinical epidemiology, it would undoubtedly accelerate the improvement of the quality of clinical practice, research, and teaching” (Luo 1991).

At the same time, other researchers have stated that the early phase of TCM RCTs in particular in China began in the early 1980s (Tang, Zhan, and Ernst 1991; Tian et al. 2021), with the first “rigorously-designed” RCT in the field of TCM published in 1982 (Chen et al. 1982). This study, conducted from August 1980 to August 1981 and published in the Chinese Journal of Cardiology, was titled “The Therapeutic Effect of Purified Coronary Heart II Tablets on 112 Cases of Angina Pectoris by Double Blind Method” and led by Keji Chen from the Xiyuan Hospital attached to the Academy of Traditional Chinese Medicine, with co-authors from Fuwai Hospital of the Chinese Academy of Medical Sciences, Beijing Tongren Hospital, and Beijing Tongrentang pharmaceutical company. However, the report lacked detailed explanations of the randomization and blinding methods beyond mentioning that “Clinical observations were carried out in two phases using a double-blind method,” and that “112 selected cases were randomly divided into Groups A and B, and were treated by a double-blind method with crossover.”

The editor’s note on this study serves as a useful indicator of contemporary thinking regarding the utility of rigorous comparisons, and the perceived limitations of contemporary studies. Indeed, such a tension between aspirations to rigor and expressions of critique would represent a recurring theme in the Chinese medical literature across TCM and Western medicine alike. As the editors commented: “This article was a well-designed study, highlighting the importance of rigorous comparisons in clinical data. They emphasized the need for credible comparisons to distinguish between true and false, better and worse, while acknowledging the challenges in achieving convincing comparisons in clinical practice” (Chen et al. 1982).

Nevertheless, they noted that the double-blind controlled method used in this study still had some limitations. The observation of 112 cases was considered an insufficient sample size, and they recommended multicenter and repeated validation. From that point, RCTs of TCM continued to expand. Tang and colleagues, extrapolating from an examination of 28 selected TCM journals, reported that from the early 1980s through the late 1990s RCTs of TCM doubled in number every two to three years, yielding an estimated total of 7500 RCTs by 1996, compared to an estimated 2500 RCTs of “conventional medicine” (Tang, Zhan, and Ernst 1991).

The 1980s likewise represented a significant turning point for the formal discussion of clinical epidemiology and clinical research methodology (Design, Measurement, Evaluation, or DME) from Western countries, and public reflection on the need for investigational rigor and attempts to support such rigor (Luo 1991; Lin 1998). In 1985, Honghao Zhou from the National Training Center for Clinical Pharmacology at Hunan Medical School published an article titled “How to Evaluate Drug Clinical Trial Reports.” In this article, Zhou proposed that the standards for evaluating a drug’s clinical trial report should be its reliability and practicality. In Zhou’s explanation, reliability referred to whether the trial results genuinely reflect the true state of affairs, which depended on the scientific nature of the experimental design and the rigor of patient observation and follow-up. Practicality pertained to whether the research results would have clinical applicability. The reliability of clinical trial results, according to Zhou, would depend first on whether controls were used and whether the participants were allocated according to the principles of randomization (Zhou 1985).

In 1986, Mengxuan Hu from Sun Yat-sen University highlighted the importance of effective clinical trial design in analyzing and evaluating the therapeutic efficacy of a drug or treatment in clinical research (Hu 1986). Hu pointed out that promoting RCTs in China faced certain (though unspecified) “difficulties”^[8], and that well-designed trials were not yet prevalent. Hu also provided an evaluation of a study published in the Chinese Journal of Neurology in 1985, conducted by Hechun Luo and colleagues from the Institute of Mental Health at Beijing Medical College, titled “Analysis of the Therapeutic Efficacy of Double-Blind Controlled Electroacupuncture and Amitriptyline in the Treatment of Depression (Luo et al. 1985).” Hu noted several reasonable aspects of the trial’s design, such as the inclusion of a control group, the use of random allocation principles (with drug dispensing randomized by the pharmacy), the application of double-blind methodology (where patients and doctors were unaware of whether the capsules contained amitriptyline or a placebo), and attention to observer bias and comparability. Additionally, appropriate statistical methods were employed. However, Hu also pointed out some limitations of the trial, such as the lack of specific details about the method of random grouping and the unequal distribution of cases among the groups.

In April 1989, under the direct leadership of the Chinese Ministry of Health, the first National Epidemiology/DME Academic Conference was held in Chengdu, initiated by West China Medical University and Shanghai Medical University. During this conference, the “China Clinical Epidemiology Network (CHINACLEN)” was formally established, with participation from a total of 44 medical schools and related institutions (Lin 1998). Guowei Lin, from Huashan Hospital, affiliated with Shanghai Medical University, has emphasized that “the establishment of CHINACLEN marked a significant milestone in the development of clinical epidemiology in China. This signified the organized and guided development of clinical epidemiology in China, and it was resolved that a national academic conference would be held every two years, along with an annual executive committee meeting” (Lin 1998) ^[9]. David Sackett, one of the principal initiators of the International Clinical Epidemiology Network, not only participated in the first National Epidemiology/DME Academic Conference in Chengdu, but would also have a profound impact on the development of clinical epidemiology and evidence-based medicine in China (Wu and Liu 2020).

Amidst such advances, critiques persisted. Zhufan Xie and Ning Li, from the Institute of Integration of Traditional Chinese and Western Medicine at the First Hospital of Beijing Medical University, conducted a methodological evaluation of therapeutic studies published in the Chinese Journal of Integrative Traditional & Western Medicine (CJIM) from 1982 to 1994 (Xie and Li 1995). They found that during this period, a total of 787 studies evaluating the efficacy of remedies were published, of which 310 were RCTs. Although the annual growth distribution of RCTs was not uniform, the percentage of RCTs increased from 11% in 1982 to 62% in 1994, covering 135 diseases and conditions, with RCTs for coronary heart disease being the most common. Xie and Li considered blinding to be an important factor in RCTs, but reported that no double-blind trials were documented in CJIM in 1982-1983. In 1984, the use of double-blinding was first reported in the examined RCTs, and only 23 RCTs over the 12 years studied used a double-blind design. They also mentioned several flaws in the RCTs they had identified, including overemphasis on significance testing, inadequate randomization, biased allocation, and publication bias, where almost all the clinical articles published in CJIM showed positive results of efficacy evaluation.

Compared to the early 1980s, the quality of clinical trials of TCM did seem to have improved gradually by the late 1980s and 1990s, as reflected in the literature of various journals. Nevertheless, critics still considered these to fall short of what by the 1990s were considered rigorous trial standards (Yu et al. 1994). Tang and colleagues, in their 1999 evaluation of TCM trials conducted from the 1980s through 1997 (Tang, Zhan, and Ernst 1991), reported that while the methodological quality of the RCTs examined had improved over time, there were still several problems, such as inappropriate descriptions of the randomization method, a lack of blinding (used in only 15% of trials), small sample sizes, the use of another Chinese medicine treatment as a control whose effectiveness had often not been established through RCTs, a lack of exploration of medium- and long-term outcomes, publication bias, and a lack of baseline characteristics. They concluded:

The quality of trials of traditional Chinese medicine must be improved urgently. Large and well designed randomized controlled trials on long term major outcomes should be funded. Subsequently, such studies may serve as models for future trials in the area… The best evidence should be systematically reviewed, summarized, and disseminated, which in turn would lead to evidence-based decision making in traditional Chinese medicine (Tang, Zhan, and Ernst 1991).

Such concerns seemed to apply to studies of Western medicine as well. Qian Wang and Boheng Zhang (Wang and Zhang 1998) conducted an investigation into the trends in research types and statistical methods used in studies published in 1985 and 1995 in five major Chinese medical journals. The authors observed an increase in the use of statistical methods in original research over the years, from 40.2% in 1985 to 60.1% in 1995. Nevertheless, despite finding that the use of “appropriate” methods also improved over time, from 22% in 1985 to 46% in 1995, more than half of the studies apparently still did not utilize “appropriate” statistical methods.

Large-Scale Multicenter RCTs and the Development of Evidence-Based Medicine (1990s onward)

Amidst such critiques, large, seemingly well-designed trials had emerged by the 1990s. Notably, researchers initiated a large-scale RCT of the ACE-inhibitor captopril in acute myocardial infarction (Wang et al. 2000). This double-blind controlled clinical trial, using a sealed envelope system with strict randomization, involved over 600 hospitals in 30 provinces, municipalities, and autonomous regions, and enrolled 14,962 patients. The pilot study finished by the end of 1989 and the trial officially started on January 1, 1990, and finished in May 1995. Interim reports were published in 1994 (Chinese CEI-AMI Trial Collaborative Group 1994) and 1995 (Chinese Cardiac Study Collaborative Group 1995; Chinese CEI-AMI Clinical Research Collaboration et al. 1995), and the final results were published in 1997 in the Chinese Journal of Cardiology (Chinese Cardiac Study-Ⅰ (CCS-Ⅰ) Collaboration Group et al. 1997).

Around the same time, demonstrating increasing collaboration between Chinese and international researchers, the Chinese Acute Stroke Trial (CAST) randomized more than 21,000 patients with acute ischaemic stroke to early aspirin or placebo in 413 Chinese hospitals, with recruitment lasting from November 1993 to March 1997 (CAST (Chinese Acute Stroke Trial) Collaborative Group 1997). These trials were followed by even larger trials in the early 2000s, including the second Chinese Cardiac Study (CCS-2), which was also called COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial). This 2×2 factorial randomized trial of adding oral clopidogrel to aspirin and of using intravenous then oral metoprolol recruited nearly 46,000 patients admitted to 1250 hospitals with a suspected acute myocardial infarction between August 1999 and February 2005 (Chen and Jiang 2009; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group 2005a; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group 2005b).

However, in the 1990s, other investigators expressed concerns that RCTs conducted in China and with results published in Chinese were not being incorporated into global databases and existing systematic reviews. Ming Liu and colleagues (Liu, Counsell, and Sandercock 1998) conducted a systematic search for stroke-related RCTs published in Chinese, manually searching the proceedings of one stroke conference and five leading Chinese medical and neurology journals that may have published relevant RCTs. From 1965 to 1995, they found 178 RCTs related to a wide range of medical specialties, constituting 1.4% of all articles in these journals, and with the majority of the RCTs not identified in MEDLINE^[10]. Although the trials were mostly small (i.e., ≤200 participants), the world’s largest randomized, double-blind, and placebo-controlled trial of blood pressure reduction on the secondary prevention of stroke, involving 5665 patients, was identified in their study and had been published in China in 1995, but was not widely cited (PATS Collaborating Group 1995).

All of this took place amidst the global rise of attention to “evidence-based medicine,” first articulated as a term in 1991 (Guyatt 1991). The term “Evidence Based Medicine (EBM)” was first translated into Chinese as “循证医学(xun zheng yi xue)” in 1996 by Jiyao Wang from Fudan University (Li et al. 2021). At the same time, Chinese scholars began introducing systematic reviews and meta-analyses (Liu 1996). In 1999, the Chinese Cochrane Center (now known as the Cochrane China Center) was formally established at the West China Hospital of Sichuan University, receiving support from the Ministry of Health of China (Li, Sun, and Wang 2008). In 2002, the Chinese Cochrane Center extended its reach by establishing a branch in Hong Kong at the Chinese University of Hong Kong SAR (Li, Sun, and Wang 2008). In 2007, the Chinese Clinical Trial Registry (ChiCTR) was officially launched, serving as a national clinical registry for China and a contributor to the World Health Organization’s international Clinical Trial Registry Platform. Its primary aim was to enhance the transparency of clinical research and reduce publication bias (Wu 2011). Since then, the number of registered clinical trials in China has continued to increase.

Artemisinin (Qinghaosu) Trials as a Telling Case Example

In 2015, the Nobel Prize in Physiology or Medicine was awarded to Youyou Tu for her role in the discovery and study of artemisinin as an antimalarial. The progression of clinical studies of artemisinin echoes most – but not all – of the trends outlined above. As indicated above, most scientific research, including clinical trials, was halted during the Cultural Revolution. However, artemisinin research officially commenced during this period. Qinghao (Artemisia annua L.) had a millennium-long history in treating malaria, dating back to the 4th century (Hsu 2006). Since the late 1950s, clinical trials utilizing Qinghao for malaria treatment gradually emerged. For instance, in 1959, Rushao Huang and colleagues published a study in the Journal of Traditional Chinese Medicine, reporting the treatment of 27 patients with symplocos chinensis (Lour.) and 18 patients with artemisia apiacea hance in the Tibetan Autonomous Region of Guangxi, observing that symplocos chinensis had inferior antipyretic effects compared to artemisia, although it apparently exhibited stronger control over other unspecified symptoms (Huang, Wei, and Zhou 1959). In 1967, the Chinese government initiated a nationwide research project named the “523 Project,” which was aimed at discovering novel therapies for malaria, leading to the discovery of artemisinin (Qinghaosu) as a new antimalarial drug (World Health Organization 2021; Tu 2011). As Youyou Tu has described this history, after an arduous investigation of more than 2,000 Chinese herbal preparations, and insights from ancient works on the preparation of Artemisia annua L. extract, they had derived the active principle from Qinghao and were ready by 1972 for clinical investigation. Yet as she has related:

During the Cultural Revolution, there were no practical ways to perform clinical trials of new drugs. So, in order to help patients with malaria, my colleagues and I bravely volunteered to be the first people to take the extract. After ascertaining that the extract was safe for human consumption, we went to the Hainan province to test its clinical efficacy (Tu et al. 2015).

These would be uncontrolled – but very promising – trials on patients with malaria. In December 1972, the drug was officially named “Qinghaosu” (Su and Miller 2015).

Large-scale clinical trials involving Qinghaosu began to be published in the late 1970s. In 1979, the Qinghaosu Antimalaria Coordinating Research Group – representing seven institutes, academies, and bureaus – published an article in the Chinese Medical Journal describing the chemical structure of Qinghaosu, pharmacological studies, and uncontrolled clinical trials, having treated 2099 cases of malaria with various preparations of Qinghaosu (Qinghaosu Antimalaria Coordinating Research Group 1979). That same year, one of the earliest RCTs involving Qinghaosu was published in the Chinese Journal of Medicine, with the researchers having randomly allocated 80 patients to either the Qinghaosu group (50 patients) or to the chloroquine control group (30 patients), with both groups achieving a cure rate of 100%, indicating that Qinghaosu oil solution could be used for severe malaria (Hubei Academy of Medical Sciences Institute of Parasitic Diseases et al. 1979). By 1984, Guoqiao Li and colleagues from the Malaria Research Unit at Guangzhou College of Traditional Chinese Medicine – along with the Roche Far East Research Foundation, Hong Kong – published in The Lancet an RCT, conducted between 1982 and 1984, aiming to assess the efficacy and side effects of combinations of mefloquine, fansidar, and Qinghaosu (Li et al. 1984). Artemisinin would thus bridge ancient and modern approaches to drug production, application, and evaluation alike.

Ethical and Enduring Epistemic Critiques and Reform

As with trial methodology, formal attention to clinical trial research ethics has had a relatively concentrated history in mainland China compared to the West. The term “Ethics Committee” was first proposed in China in the late 1980s, leading to the establishment of such committees in various hospitals over the next decade (Tian 2006). However, during this period, the ethical review of scientific research was not widely practiced, with such committees focusing primarily on medical ethics education and the development of professional conduct (Zhang, Zhang, and Zhao 2016). Towards the end of the 1990s, there was a notable increase in the number of Ethics Committees focusing on ethical review of biomedical research involving human subjects. These committees were not only established in hospitals but also in the majority of medical schools, large pharmaceutical research institutions, and biomedical technology companies.

Since 2000, China has accelerated efforts to institutionalize research ethics. That year, the Ministry of Health established the first session of the Expert Committee on Medical Ethics, tasked with researching ethical issues in medical research and providing recommendations for ethics education. In 2003, the State Food and Drug Administration issued “Norms on Quality Management of Drug Clinical Trials,” which mandated certification for all medical institutions conducting clinical trials and the establishment of independent research ethics committees registered with the administration. The aim was to safeguard the rights and interests of all participants and applicants involved in clinical trials (Wu et al. 2010). In 2010, ChiCTR established the Chinese Ethics Committee of Registering Clinical Trials (ChiECRCT). ChiECRCT proposed the establishment of an ethical review system while simultaneously integrating the registration of clinical trials with ethical review. This initiative aimed to facilitate the registration of clinical trials in China and improve the overall quality of clinical trials (Wu et al. 2010).

Although there has been an increasing emphasis on the importance of ethics and informed consent starting in the 21^st century, this transformation remains incomplete and continues to be scrutinized. After analyzing clinical research articles published in 1998 across 14 biomedical journals in China regarding the disclosure of informed consent, Mouyue Wang found that only 1% of the clinical studies reported obtaining informed consent (Wang 2000). Nearly two decades later, Hongjie Zhao and colleagues found that, among 395 clinical RCTs published in the top 20 medical journals with high impact factors and indexed by the China Science Citation Database (CSCD) during 2016-2017, only 46.8% of the trials reported having undergone ethical review and 64.1% of the trials obtained informed consent. While the quantity of ethical reviews had substantially increased compared to a decade prior, the authors suggested that the ethical review platform was still not robust, emphasizing the need to improve awareness and accessibility of ethical review processes (Zhao et al. 2018).

With the increasing number of clinical trials conducted in China, it has also faced ongoing criticism concerning the validity of such trial results. In 2007, an article published in the Lancet titled “Reforming Research in China” pointed out that, in 2006, there were several allegations^[11] of scientific misconduct in China, though there appeared to be a positive shift in 2007 (Anon 2007). In response to such criticism, the Chinese Ministry of Science and Technology issued its Measures for Handling Scientific Research Misconduct in the Implementation of National Science and Technology Programs (Trial) to address misconduct in nationally funded programs (Central People’s Government of the People’s Republic of China 2006). Additionally, the Chinese Academy of Sciences published a Declaration of Scientific Ideology (Central People’s Government of the People’s Republic of China 2007). In 2007, China officially established the ‘Joint Meeting System for Research Integrity Construction’ (in Chinese as “科研诚信建设联席会议制度”), involving six departments and units, including the Ministry of Science and Technology, the Ministry of Education, the Chinese Academy of Sciences, the Chinese Academy of Engineering, the National Natural Science Foundation of China, and the China Association for Science and Technology (Lu and Jiang 2011). As the Lancet article concluded:

Ethical principles can guide all stages of research. If grant awards are transparent, institutional review boards invite debate, participant autonomy is respected, and analysis and presentation of findings is accountable, then China has the opportunity to lead the world not only in research quantity, but also in quality (Anon 2007).

And yet, critiques persisted. In the early 21st century, western countries had already begun adopting The Consolidated Standards of Reporting Trials (CONSORT) statement, aimed at improving the quality of RCTs. This statement was officially introduced in China in 2001 and formally translated into Chinese in 2007 (Song et al. 2015). In 2008, Dalu Zhang and colleagues from the University of Birmingham published a paper in Trials with the intention of assessing the quality of Chinese RCTs published in English in 2004 (Zhang et al. 2008). The authors noted that “this is the first systematic study to evaluate the quality of trial conduct and reporting in a sample likely to be more representative of Chinese RCTs in general.” Among the 307 RCTs included in the study, 199 (64.8%) failed to report their randomization methods, and 254 (82.4%) did not mention blinding of either participants or investigators. Fewer than 11% of RCTs mentioned ethical approval, and only 18.0% were reported to have adequately discussed informed consent. Notably, nearly 44% of trials reported a zero dropout rate. Simultaneously, research indicated that until 2011, only eight Chinese-language journals had officially listed the requirements of the CONSORT Statement in the “Introductions to authors” (Song et al. 2015; Li et al. 2012). In contrast, 458 major international peer-reviewed medical journals on PubMed had endorsed the CONSORT statement before 2011 (Song et al. 2015).

During this same period, Taixiang Wu and colleagues reported that among 3137 RCTs (1452 in conventional medicine and 1685 in TCM) published in Chinese and conducted from 1994 to 2005, only 6.8% of these trials could be considered “authentic,” adhering “to accepted methodology for randomization,” as ascertained through interviews with the authors of the reports (Wu et al. 2009).^[12] Likewise, Jia He and colleagues proposed in the Lancet that the most common design errors in Chinese biomedical research pertained to sample size estimation and randomization, such as the absence of formal estimation or the use of an incorrect formula for sample size calculation, as well as the failure to describe the randomization procedure or casually mentioning it (He, Jin, and Yu 2009).

In this context, in 2010, Jiyao Wang discussed in the Lancet that the growth of evidence-based medicine in China presented both challenges and opportunities (Wang 2010a). Notably, between 1999 and 2008, only 0.21% of clinical research articles published in the New England Journal of Medicine, the Lancet, or JAMA originated from mainland China (Wang 2010b). Consequently, Wang proposed recommendations for improving research quality and transparency, covering clinical trial registration, management platforms, ethics, and reporting standards. She concluded by referencing the Lancet’s 2007 statement concerning “reforming research in China” (Anon 2007): “There is a long way to go before the words of a Lancet Editorial—’China has the opportunity to lead the world not only in research quantity, but also in quality’—are fulfilled” (Wang 2010a).  A year later, Yonghua Hu and colleagues, in their 2011 Lancet analysis of the current status of clinical research in China, echoed such concerns about China’s global presence.  They noted that while the number of published RCTs in China reported in PubMed had increased from 85 in the year 2000 to 743 in 2009, these RCTs accounted for only 1.7% of RCTs published globally (Hu et al. 2011).

As of 2013, China was therefore still considered to have remained a country that primarily imported medical evidence rather than exporting it, owing to the inadequacy of “robust clinical research and data” (Wang and Liu 2013). To enhance clinical research, in 2013, the Chinese government officially launched 13 national-level clinical research centers among six key areas (Ministry of Science and Technology of the People’s Republic of China 2013). This number increased to 20 common diseases and frequently occurring conditions by 2022, with the establishment of 50 national-level clinical research centers (Central People’s Government of the People’s Republic of China 2022). Chen Wang and Qian Liu pointed out in the Lancet in 2013 that China’s substantial disease burden can actually serve as a valuable clinical resource for physicians to design clinical research and gather clinical data (Wang and Liu 2013). Yet many trials, it appeared, would turn out to be “redundant,” yielding results that had already been established (e.g., the utility of statins in patients with coronary artery disease) and therefore violating notions of clinical equipoise (Jia et al. 2021).

In recent years, in addition to those concerning Western medicine, clinical trials involving TCM and acupuncture have also garnered significant attention to increasing the quality of evidence. In 2017, researchers from Hong Kong SAR, mainland China, UK, and Canada published the CONSORT extensions for Chinese Herbal Medicine (CHM) formulas, hoping it could improve the reporting quality of CHM formulas (Cheng et al. 2017). In 2022, the BMJ released a collection of articles titled “Acupuncture: How to Improve the Evidence Base” (Anon 2022). This series analyzed the progress of high-quality research in acupuncture, summarized the current status, and provided evidence-based guidelines for designing high-quality acupuncture trials (Zhang et al. 2022). In 2023, the China Academy of Chinese Medical Sciences and the China Center for Evidence Based Traditional Chinese Medicine operated the International Traditional Medicine Clinical Trial Registry (ITMCTR), which became a member of the primary registry network of the International Clinical Trials Registry Platform (ICTRP) and added to the ICTRP database. It is the first formal registration platform for traditional medicine, and through Feb 14, 2024, a total of 4,246 trials have been registered (International Traditional Medicine Clinical Trial Registry 2022).

Thus, in recent decades, Chinese researchers have taken a self-reflective stance on the conduct of clinical research in mainland China. They have generally described an incomplete transition to this point, against the backdrop of similar developments outside of China, and the unique relationship between conventional medicine and TCM. We see an enduring tension between enthusiasm for the opportunities for clinical trial expansion, and concerns regarding the limits of existing efforts.

Conclusion

In 2022, it was estimated that nearly 28% of all clinical trials, globally, were conducted in China (Clinical Trials Arena 2023). And yet persisting attention has focused on the limitations – ethical and methodological – to such trial activity (Fan et al. 2022). As this overview has shown, such a dynamic between growth, self-reflection, and critique is not new, but has characterized China’s RCT landscape for over seven decades.

Some of these enduring growth pains may be ascribed to the relatively rapid evolution of RCTs in China. And yet, this is an older and richer history than has been conventionally described. This history – serving as the backdrop to current trial expansion – illustrates the co-development of methodology, medicine(s), the state, and the larger global contexts in which Chinese medicine has developed.

We have provided a prelude to additional and more nuanced and contextualized examinations. Scholars examining the evolution of RCTs in the west have the benefit of a robust historiography, and rich databases like the James Lind Library. There is no equivalent Ben Cao Tu Jing Library of the history of “fair tests of treatment in healthcare” in China. At least not yet. We hope to have made a useful start, and invite others to join in this work and further enrich our understanding of the history of clinical trials in China.

 Acknowledgments

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

Funding

The National Social Sciences Foundation of China: ‘Research on the Theoretical System, International Experience and Chinese Path of Evidence-based Social Science’ (Project No. 19ZDA142).

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Footnotes:

[1] They likewise serve as important primary source documents in their own right, as they have often been framed in terms of self-reflection and critique, arguing for improved methodological rigor and ethical oversight.

[2] Note that Lei states that Blake “decided in 1903 to conduct a controlled experiment to compare patients treated with Western medicine and those treated with Chinese medicine” (p. 32). The actual “experiment” (Blake, 1903, pp. 11-12) appears to have been a retrospective comparison between patients treated at home with TCM, and those in the hospital with Western medicine, admittedly during the same time period in the same city.

[3] “Paracholera” in Chinese is “副霍乱”.

[4] Using full-text searching of the China National Knowledge Infrastructure (CNKI), we conducted a search for “苏德隆” (Su Delong) and “随机对照” (randomized control) on January 9, 2024, and examined the book named Collected Papers of Professor Delong Su (Su 1955).

[5] Note that all translations from the Chinese medical literature in this article have been rendered by Xuan Yu.

[6] “Random sampling method” in Chinese is “随机抽样方法”.

[7] “Furapromidium versus a combination of adrenocortical hormones (prednisone) and antimony potassium tartrate” in Chinese is “呋喃丙胺及泼尼松合并酒石酸锑钾”.

[8] Hu mentioned it in Chinese as “临床试验尤其是随机对照试验在我国推广尚有一定的困难”.

[9] In 1993, during the 3^rd National Conference on Clinical Epidemiology/DME held in Guangzhou, the Clinical Epidemiology Association of Chinese Medical Association was formally established. This marked the official integration of China’s clinical epidemiological academic activities under the unified leadership of the Chinese Medical Association. In 2013, the Clinical Epidemiology Association of Chinese Medical Association was renamed as the Clinical Epidemiology and Evidence-Based Medicine Association of Chinese Medical Association. In August 2023, the 21^st academic conference was convened in Lanzhou, Gansu Province. From August 15 to 18, 2024, the 22^nd academic conference was convened in Sichuan, Chengdu Province.

[10] The authors mentioned in the results section that they found two RCTs from 1965 to 1983; unfortunately, the authors did not specify which two papers they were referring to.

[11] The article did not specify exact allegations. Through searches on Baidu and Google, it was found that a serious scientific research fraud case occurred in China in 2006—the Hanxin Project: https://www.nytimes.com/2006/05/15/technology/in-a-scientists-fall-china-feels-robbed-of-glory.html. Moreover, Nature Medicine (Jia 2006) published an article in 2006 titled “Frequent cases force China to face up to scientific fraud,” mentioning six high-profile cases of scientific misconduct over eight months: “for China’s biomedical research, still struggling for global credibility, the frequent accusations of plagiarism, falsified data and fabricated resumes spell out a serious warning—one that the government is finally preparing to heed.”

[12] “A randomization sequence generated from a random number table, calculator or computerized random-number generator was considered authentic.  Coin-tossing or drawing straws in the presence of the participant to decide which group he or she would be assigned to were considered ineligible randomization techniques.  Allocation of participants according to date of birth, or their hospital record number, or the date on which they were invited to participate (for example, an odd or even day) was not considered adequate” (Wu et al. 2009, p. 3).