Type 2 diabetes RCTs in mainland China: insights from a systematic review

Diabetes has become an epidemic worldwide and in China. Diabetes in Chinese adults has distinct features in genetic background and pathophysiological process from diabetes in white populations of European ancestry.1Chan JC Malik V Jia W et al.Diabetes in Asia: epidemiology, risk factors, and pathophysiology.JAMA. 2009; 27: 2129-2140Crossref Scopus (1494) Google Scholar, 2Wang T Lu J Shi L et al.Association of insulin resistance and β-cell dysfunction with incident diabetes among adults in China: a nationwide, population-based, prospective cohort study.Lancet Diabetes Endocrinol. 2020; 8: 115-124Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar Despite this fact, clinical practice guidelines for the management of diabetes in Chinese adults are very similar to guidelines for Europeans and North Americans because evidence from high-quality randomised controlled clinical trials (RCTs) in Chinese patients is scarce. Rigorously designed and effectively conducted RCTs are needed in the face of a continuing challenge from this rising diabetes burden to tailor specific treatment and prevention strategies in China. To provide an overview of type 2 diabetes RCTs in China, including general information and specific trial characteristics, and to identify limitations in the conduct of the trials with the aim of improving diabetes research, we systematically searched published articles from English-language journals and records of registered trials from clinical trial registries for type 2 diabetes RCTs done in mainland China over the past three decades. The detailed study methods are provided in appendix 1. We searched for trials published from database inception up to Aug 31, 2020, and studies were included if they enrolled people with type 2 diabetes from mainland China and participants were randomly assigned to different intervention groups. Multinational studies that enrolled Chinese participants were also included. Study selection is described in appendix 2 and the information extracted from each included trial is listed in appendix 3. 1044 trials were included: 960 (92·0%) were done within mainland China and 84 (8·0%) were multinational studies that included Chinese participants. Characteristics of the included trials are summarised in appendix 2. More than half (62·6%) of the trials were done in patients with only type 2 diabetes, followed by trials done in patients with type 2 diabetes with complications (28·4%) or comorbidities (9·0%). The majority (66·6%) of trials examined pharmacological treatments, followed by behavioural interventions (10·3%), procedures (6·4%), dietary supplements (5·2%), biological therapies (4·1%), and devices (1·5%). Numbers of trials by patient and intervention categories are shown in the figure. Numbers of RCTs in patients with type 2 diabetes done in mainland China increased dramatically between 2000 and 2010 (figure, appendix 2). Before 2000, trials were done sporadically and were often not reported. The number increased rapidly after 2000 before plateauing from 2010, with about 60 newly started trials each year. In 2019, the number continued to rise and nearly doubled. Geographical distribution of primary investigators of trials done over the past three decades across mainland China was uneven. Eastern China was most actively involved, accounting for 73·7% of all trials in type 2 diabetes done in mainland China (figure). Western, middle, and northeast China accounted for 13·3%, 9·2%, and 3·8%, respectively (figure). Most of the trials had small study populations (excluding multinational trials). Only 85 (8·9%) trials enrolled more than 500 people, and 364 (37·9%) trials had fewer than 100 participants (appendix 2). 275 (26·3%) trials were open label, 56 (5·4%) trials were single blinded, and 232 (22·2%) trials were double blinded (appendix 2); however, 394 (37·7%) trials did not mention type of blinding. Most trials (81·9%) had a duration of less than 48 weeks (appendix 2). Among 466 trials with available data (excluding multinational trials), loss to follow-up was less than 5·0% in 211 trials, 5·0–9·9% in 88 trials, 10·0% or higher in 127 trials, and not mentioned in 40 trials (appendix 2). Loss to follow-up was generally more substantial in trials of behavioural intervention and in trials with longer duration of follow-up. Although type 2 diabetes RCTs in mainland China have progressed remarkably over the past three decades, our systematic review identified several problems. Most trials enrolled fewer than 500 participants and had a period of intervention shorter than 48 weeks. Information on use of blinding and randomisation procedures were often missing, assumptions for the calculation of sample sizes were rarely stated, potential biases in the conduct of trials and analysis of trial data were often not discussed, and the primary outcome was usually not identified (appendix 2). Most trials were published in specialist diabetes journals rather than major general medical journals. More than half of the published RCTs did not report trial registration identification numbers (appendix 2). In a global analysis of RCTs published in all PubMed-indexed journals in 2018, 71·2% of 10 500 articles reported the trial registration number,3Al-Durra M Nolan RP Seto E Cafazzo JA Prospective registration and reporting of trial number in randomised clinical trials: global cross sectional study of the adoption of ICMJE and Declaration of Helsinki recommendations.BMJ. 2020; 369: m982Crossref PubMed Scopus (24) Google Scholar compared with 48·1% of Chinese diabetes trials published in 2018 in our review. Although the four clinical trials registries used for our search were all certified by the WHO International Clinical Trials Registry Platform, trial characteristics such as inclusion and exclusion criteria, use of blinding, randomisation procedures, and institutions involved in the registered trial could still be missing for many trials. The status of many trials is often unknown and major findings of completed trials are rarely submitted in clinical trials registries. 10·6% of Chinese type 2 diabetes RCTs on ClinicalTrials.gov submitted results within 1 year of completion, compared with 40·9% of all registered trials due to report results on ClinicalTrials.gov from March 2018 to September 2019.4DeVito NJ Bacon S Goldacre B Compliance with legal requirement to report clinical trial results on ClinicalTrials.gov: a cohort study.Lancet. 2020; 395: 361-369Summary Full Text Full Text PDF PubMed Scopus (81) Google Scholar Globally, trial registration and reporting have improved over time, however, poor compliance is still a problem.3Al-Durra M Nolan RP Seto E Cafazzo JA Prospective registration and reporting of trial number in randomised clinical trials: global cross sectional study of the adoption of ICMJE and Declaration of Helsinki recommendations.BMJ. 2020; 369: m982Crossref PubMed Scopus (24) Google Scholar, 4DeVito NJ Bacon S Goldacre B Compliance with legal requirement to report clinical trial results on ClinicalTrials.gov: a cohort study.Lancet. 2020; 395: 361-369Summary Full Text Full Text PDF PubMed Scopus (81) Google Scholar Notably, we did not include RCTs published in Chinese-language journals and we acknowledge that this language bias is a limitation of our analysis. Our systematic review has important implications for future diabetes research in China and might also be useful with respect to research in other countries facing similar economic growth and a rising diabetes burden. Diabetes-related complications are a major driver of disease burden, and longer life expectancies in Chinese people have led to increased diabetes complications, including cardiovascular disease, chronic kidney disease, certain cancers, and major cognitive impairment.5Huo X Gao L Guo L et al.Risk of non-fatal cardiovascular diseases in early-onset versus late-onset type 2 diabetes in China: a cross-sectional study.Lancet Diabetes Endocrinol. 2016; 4: 115-124Summary Full Text Full Text PDF PubMed Scopus (142) Google Scholar However, only 37 (3·5%) trials of type 2 diabetes investigated outcomes of complications such as cardiovascular disease, proliferative diabetic retinopathy, and end-stage renal disease, among which 19 were multinational trials. These trials often require large numbers of participants and long durations of follow-up, and hence substantial increases in study cost, time, and personnel. Nevertheless, resources should be pooled in the future to fund well designed outcome trials in Chinese patients with diabetes, since findings from these studies often change clinical practice. In our systematic review, 11 (1·1%) studies were found to be related to self-monitoring or treatment adherence. Trials of this kind are important,6Xavier D Gupta R Kamath D et al.Community health worker-based intervention for adherence to drugs and lifestyle change after acute coronary syndrome: a multicentre, open, randomised controlled trial.Lancet Diabetes Endocrinol. 2016; 4: 244-253Summary Full Text Full Text PDF PubMed Scopus (81) Google Scholar but were far fewer in number than other types of intervention in Chinese type 2 diabetes trials. Future RCTs should focus on patients in resource-limited settings, and aim to identify easily accessible and broadly applicable solutions for disease management that have the potential to benefit a broad patient population. The use of RCTs for clinical research of diabetes is at an early stage in China. Fortunately, research funding for RCTs from the central and local governments, universities, research institutions, and hospitals has increased substantially. Since 2013, China has established 50 national clinical research centres covering major disease areas such as diabetes, cardiovascular disease, stroke, and cancer to foster innovation and collaboration in clinical research, especially RCTs. For drug and medical device approval, the central government enacted a guideline on Oct 9, 2017, to encourage innovation in drugs and medical equipment by expanding the reform of the review and approval system.7The State CouncilThe People's Republic of ChinaChina to encourage innovation in drugs, medical equipment.http://english.www.gov.cn/policies/latest_releases/2017/10/09/content_281475902090770.htmDate: Oct 9, 2017Date accessed: December 11, 2020Google Scholar According to the guideline, non-state funds are encouraged to invest in clinical trial institutes, and medical organisations, research institutes, and colleges are supported to do clinical trials.7The State CouncilThe People's Republic of ChinaChina to encourage innovation in drugs, medical equipment.http://english.www.gov.cn/policies/latest_releases/2017/10/09/content_281475902090770.htmDate: Oct 9, 2017Date accessed: December 11, 2020Google Scholar In response to the reform, the numbers of initiated clinical trials in type 2 diabetes has rapidly increased since 2018. Meanwhile, the Chinese drug market has become the second largest in the world;8Mullard A Chinese biopharma starts feeding the global pipeline.Nat Rev Drug Discov. 2017; 16: 443-446Crossref PubMed Scopus (19) Google Scholar as such, more high-quality clinical trials are foreseeable in China in the near future, which could also produce evidence that can be useful in other countries. China has the largest population of patients with diabetes in the world, and these patients have huge unmet medical needs.9Ye L Xu J Zhang T et al.Global burden of noncommunicable diseases attributable to high fasting plasma glucose.J Diabetes. 2020; 12: 807-818Crossref PubMed Scopus (6) Google Scholar Efforts are needed to promote medical innovation and develop effective treatment strategies via evidence-based medicine. Proper trial registration and timely reporting of results are important in standardising trial conduct and reducing publication bias. Enforcement from regulators and responsibility of investigators need to be reinforced, to improve registration and reporting compliance, to increase trial transparency and accountability, and eventually to provide high-level evidence for clinical practice guidelines. We declare no competing interests. RZ and YuX contributed equally. RZ, YuX, YB, WW, and GN designed the study. RZ and YuX independently searched the scientific literature and trial registries and extracted data. JN, SWu, ML, JL, SWa, and YB contributed to the interpretation of the data. RZ, YuX, and YB drafted the Correspondence. JN, ShuW, ML, JL, YiX, WW, and GN revised the Correspondence critically for important intellectual content. All authors agreed to be accountable for all aspects of the work and approved the final submitted version of the Correspondence. This work was supported by grants from the National Key Research and Development Program of China (2017YFC1310700, 2016YFC1305600, 2018YFC1311800, 2016YFC0901200, 2016YFC1305202, and 2016YFC1304904), the National Science and Technology Major Project for Significant New Drugs Development (2017ZX09304007), the National Natural Science Foundation of China (81561128019, 81621061, 81700764, and 81870560), the Shanghai Municipal Government (18411951800), the Shanghai Shenkang Hospital Development Center (SHDC12019101), the Shanghai Jiaotong University School of Medicine (DLY201801), and the Ruijin Hospital (2018CR002). YB was supported by the Shanghai Outstanding Academic Leader Program and YuX was supported by the Outstanding Young Talent Program from the Shanghai Municipal Government. The funders of the study had no role in study design, data collection, data interpretation, or writing of the Correspondence. RZ, YuX, YB, and GN had full access to all data in the study and verified the data. The corresponding authors had final responsibility for the decision to submit for publication. The Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations. Download .pdf (.39 MB) Help with pdf files Supplementary appendix 1 Download .pdf (1.22 MB) Help with pdf files Supplementary appendix 2 Download .xlsx (.23 MB) Help with xlsx files Supplementary appendix 3