Jin-Hua Si,Nan Li,Liang Du,Yao-Long Cheng,Hong-Cai Shang

1Tianjin University of Traditional Chinese Medicine,Tianjin,China.2Medical Identification Center，Jiangsu Medical Association,Nanjing,China.3Chinese Evidence-Based Medicine Center,West China Hospital,Sichuan University,Chengdu,China.4Evidence-Based Medicine Center,School of Basic Medical Sciences,Lanzhou University,Lanzhou,China.5Key Laboratory of Evidence-Based Medicine and Knowledge Translation of Gansu Province,Lanzhou,China.6Chinese GRADE Center,Lanzhou University,Lanzhou,China.7Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing,Dongzhimen Hospital,Beijing University of Chinese Medicine,Beijing,China.

Introduction

TheefficacyevaluationoftraditionalChinese medicine(TCM)is mainly based on TCM doctors’experience and the patients’subjective experience,which is poor in repeatability or non-repeatable as clinical evidence.This affects the scientific and objective evaluation of the clinical efficacy of TCM and hinders the modernization of TCM.Therefore,it is of great importance to improve the designing ability of clinical trial methodology and establish suitable efficacy evaluation indicators and evaluation timings for the TCM efficacy evaluation in light of the characteristics of TCM.Bycollecting and summarizing TCM clinical researches published in internationaljournals,thisessaywillestablish TraditionalChineseMedicineClinicalResearch Protocol Database(TCMCRPD),aiming to provide new references for the clinical research design and new evaluation methods for the TCM efficacy.This is of great value to the development of TCM research,to the guidance of the TCM clinical practice,and to the promotion of the international exchange and communication of TCM.

Currentproblems in TCM clinical research protocols

Using the following keywords such as TCM,Chinese Herbal Drugs,Clinical Trial,Clinical Study,random*,blind*,single-blind*,double-blind*,treble blind*,triple-blind*and so on,this essay conducted a literature search for the last 20 years in PubMed database.The results show that with the introduction of clinical epidemiology,evidence-based medicine and the criterions for the quality control of clinical trial of drugs in recent years,the number of TCM clinical researches increased rapidly over the past 20 years(Figure 1).However,theassessmentofreportquality demonstratedthatresearchqualitywasstill unsatisfactory,including defects in methodology[1-3],poor homogeneity of researches and copying the western medicine mode.As a result,some researchers drew the conclusion that the efficacy of TCMisuncertaineveninvalidaccordingto systematic reviews[4].It could not show the real effect and value of TCM.

Methodology aspects

RandomizedMethodsandAllocation ConcealmentThemisuseorabuseof“randomization”is commonly seen in many TCM clinical research reports[5].At present,most TCM clinical trials in China do not clearly describe the generation of random sequences or the allocation concealment. “Randomization” isonlybriefly mentioned in these research reports.Researchers do not make detailed descriptions of the generation of allocation sequences or allocation proportion as well as random types.

Control Group is UnreasonableIn TCM clinical studies,researchersseektheconclusionabout non-inferiority of TCM or equivalence of TCM when compared with positive medicine.In a non-inferiority or equivalence trial,it is likely to ascribe special cases which are in a critical state to effective cases by positive control agent with randomized and blind that greatly increase the chance of non-inferiority or equivalence[6].According to medical ethics,blank or placebo control won’t be chosen when there are effective drugs.Researchers must try to choose western medicine with precise effect as drug control.The efficacy of many TCM drugs is not clear,so they cannot be used as the control group.

Figure 1 The temporal distribution of the literatures about clinical research of TCM in PubMed

Blinding methodBlinding method,as an important way to control and reduce the measurement bias,must be applied during the whole process of the study.Even so,there still exist a number of problems intheblindedtrials.Forexample,insome double-blind and double simulated studies,it is difficult to get simulation agents which are the same as the experimental drugs.It is very possible to lead to the breaking of the blinding[7].In many TCM trails,a blinding method is only briefly mentioned in research reports,researchers do not make a detailed description of the object of blinding or how to conduct the blinding.In addition,many operational interventions of TCM,such as acupuncture and cupping,are difficult to be blind.It is not suitable to adopt the blinding method to these interventions.

Sample SizeThere is a great difference between the TCM clinical trials and international multi-centered clinical trials for the sample size.In the TCM clinical research,researchersdon’tmakeadetailed description of the sample size calculation method,such as whether to calculate the sample size by the pilotexperimentdata,whethertoinvolvethe statistician and whether to consider enough strength testing.Due to the inadequate calculation basis,it often leads to inaccurate results.

Homogeneity of TCM Clinical Research Varies Greatly

Many factors could affect the efficacy of TCM,especially the syndrome quantization[8].At present,the syndrome of Chinese medicine lack uniform standards and quantitative indicators,as a result,different TCM experts often have different criteria to diagnose the same disease and syndrome.The lack of a recognized syndrome quantitative criteria affects the reference value of syndrome indicators[9].Different indicators(symptoms and signs)in the different syndrome play the different weighted values,forexample,whentheexteriorsyndromeis diagnosed,aversion to cold and floating pulse is more important than the fever,headache,sore throat and other symptoms[10].Therefore,when the primary and secondary symptoms are assigned to different weights simply,it is difficult to quantify syndromes objectively.In addition,TCM stress syndrome differentiation and treatment,but it is not conducive to evaluate the efficacy of TCM clinical trials while some researchers choose complicated disease syndrome even with some excessive and accompanying syndromes.

TCMclinicaltrailCopyWesternMedicine Clinical Trials Research Mode Mechanically

The current mode of TCM clinical diagnosis and treatment always combine western medicine disease diagnosis mode with Chinese medicine syndrome,therefore TCM clinical researchers usually copy the clinical efficacy evaluation mode and outcomes which based on western reductionism.Chinese and western medicine is different from the treatment method and target.If TCM clinical researchers ignore characteristics of syndrome differentiation and complex interventions but only use biologically related indicators to evaluate TCM efficacy,it is insufficient and one-sided.Furthermore,the simple and indiscriminate application of the randomized controlled trial(RCT)method cannot explain the true efficacy of TCM accurately[7].RCT studies require standardized treatment and unified disease diagnosis criteria which based on a laboratory test.But TCM makes a diagnosis based on correlation of all four examinations by a doctor,it has been considered subjectively.When treatment for the disease,TCM according to syndromes with combination therapy,different people with different treatment and varies with time,and different TCM doctors diagnosis syndromes may not be consistent,that lead to findings are difficult to repeat[4].In practice,we found that the scope of observational studies,single case RCT,practical RCT are wider to some extent,thesemethodsaresuperiortoreflectthe characteristicsofTCMclinicalefficacy[4].Moreover,evaluatetheadvantagesofChinese medicine research methods cannot be an RCT.

In addition,how to select the proper efficacy assessment indicators is a common problem in the TCM clinical research.Most TCM researches of the similar categories use different efficacy indicators.Many TCM clinical types of research only report the results of trails with simple and broad expressions,such as effective or with significant effect.These expressions are difficult to describe the efficacy of TCM objectively[8].How to establish a TCM efficacy evaluation indicator system and clarify the reciprocal relations of these indicators has become a major problem in the clinical evaluation of TCM.

The necessity to Establish TCMCRPD

TCMCRPD is Important for TCM Research

Research protocols record the research purpose,the study population,intervention,research methods,statistical methods,and provide a basic guideline for researchers to carry out clinical trials,for participants it describes research methods in detail;for the ethics committee,it is a prior document to understand the safety and interests of the participants,for the system review authors and peer reviewers,it provides an important material to evaluate potential bias of clinical research[9].Furthermore,when clinical researchers design a new clinical trial,they can learn the protocols that our database included for reference to ensure that new research more scientific and reliable.

In the meantime of preserving the characteristic of treatingdiseasesaccordingtosyndrome differentiations of TCM,it is crucial to promote the standardization of the efficacy evaluation of TCM[10].Throughthedeepminingofthedata,TCMCRPD may be able to inspire users to come up with more appropriate clinical efficacy evaluation methods or provide directions as well as key points for further studies of TCM research.For example,researchers may discover that TCM has important advantages in some parts of the treatment for some diseases through the clinical research protocol.This would remind researchers to pay attention to these advantages when developing new TCM drugs,which is important for the R&D of new TCM drugs.

Guidance on Clinical Practice of TCM

BylearningtheTCMclinicaltrialprotocols,understanding the key information of clinical trials,TCMclinicalpractitionerscanimprovetheir knowledge and combine theory with practice.Then,in clinical practice,they can learn the regularity of treatment protocols and effective interventions and grasp the key time-points of TCM intervention when treating a specific disease.At the same time,they can also improve the curative effect and the clinical diagnosis-treatment level constantly.

The effectiveness and safety of Chinese medicine to be fully reflected in clinical practice,it will help enhance clinicians further study enthusiasm,promote thinking and scientific interest,forming a virtuous circle,making diagnosis-treatment level can be sublimated.

Feasibility to Establish TCMCRPD

The introduction of evidence-based medicineThe introductionoftheideasandmethodsof evidence-based medicine into the clinical research of TCM will undoubtedly inject new strength to the development of TCM.With the combination of EBM and TCM,the concept of evidence-based TCM has beengraduallydeveloped.ItensuresTCM researchers produce more authentic evidence in scientific research and select interventions based on thebestevidenceinclinicalpractice[11].Furthermore,it can use a systematic review to evaluate TCM clinical diagnosis-treatment methods or develop more objective treatment guidelines,at the same time,seek out the preponderant disease or methods which may be suitable for evaluating the efficacy of TCM.In a word,it is beneficial to make our database scientific and normative while applying theconceptsandmethodsofevidence-based medicine in TCM clinical research protocol design.

Guideline of protocol items for clinical trials was developed

In order to improve the protocol contents of clinical trials,some international organizations launched the standard protocol items：recommendations for interventional trials(SPIRIT)initiative in 2007 and revised in 2013.The SPIRIT 2013 Statement was developed in broad consultation with 115 key stakeholders.As detailed later,the SPIRIT guideline was developed through 2 systematic reviews,a formal Delphi consensus process,2 face-to-face consensus meetings,and pilot testing,it includes a 33-item checklist and diagram[12].

The primary scope of SPIRIT 2013 relates to RCT,but the same considerations substantially apply to all types of clinical trials,it provides a very important reference for TCM clinical trials,and our database will take a full consideration with items of SPIRIT 2013.

Registration and transparency of clinical trials

Clinicaltrialsregistrationisveryusefulto transparency and comprehensiveness of the content in the design of clinical trials.Nowadays,clinical trials registration attaches great importance by many countries all over the world.Since 1977 the United States established the world's first clinical trial registrationcenter,moreandmoreregistration centers have followed and running,such as the British international randomized controlled trials registry,Australian-NewZealandclinicaltrials registry,China clinical trials registry[13-16].

InternationalCommitteeofMedicalJournal Editors(ICMJE)requires all clinical trials must be registered before publish or the results will not be published[17].WHO recommended a simplified item list except clinical trials registration number to maketheclinicaltrialregistrationinformation comprehensive.This received the acceptance from ICMJEandotherjournaleditorsorrelevant legislative departments.

Specification for clinical trial registration provides a platform to TCM clinical trial registration,and put forward the high requirements of clinical trial design quality of TCM,registered clinical trials could obtain method guidance from the registered institutions,and make the design and implementation more optimized,which provides the basis material for establishing high-quality protocol database of TCM[18].

In addition,it has become a global consensus that through the development and implementation of clinical trials report specification to promote the clinical trials quality and transparency.Enhance Quality and Transparency of Health(EQUATOR)collaboration network was initiated at the Royal Society of medicine in 2008,so far,EQUATOR has developed and published 328 guidelines for reporting and updating medical research,the report greatly promoted thestandardizationof TCMresearch reports on transparency and accuracy,and it also guarantees the materials that our database will include reliability and value.

TheTechnologyRoadmaptoEstablish TCMCPD

The establishment of Protocol Database for TCM Clinical research will be divided into two steps:collection and processing of the literature data;design and building of the database.The technology roadmap is shown in Figure 2[19].We will search PubMedandEMbase,whicharefamous internationalbiomedicalretrievalsystems.After removing the duplicate documents,we will screen out the research reports which meet the inclusion and exclusion criteria,then,extract general information,such as country,title,author,journal,publish year,diseases,interventions,outcomes,study type and so on PICOS elements.Then we establish the relational database from the actual demand,the database will realize the data input,system maintenance(include query and modify,delete,audit,data import,and export),and statistical analysis.Finally,we will input the clinical research literature of Chinese medicine treatment of coronary heart disease as an example to test the effectiveness of the database.

Conclusions

Recently,Chinese researchers published a paper about acupuncture treatment for chronic severe functionalconstipationatthetopinternational medical journal"Annals of Internal Medicine"the trial was a large-scale acupuncture RCT which completed by Chinese researchers,this study has somecharacteristics,theyarerigorousdesign,scientific observation indicators,rich case samples,standardizedandunifiedclinicalspecification,repeatableinterventions,andobtainmeaningful results,so the result received wide recognition,at the same time,it can be concluded that the TCM clinical trials which are strictly designed and implemented can reach a reliable conclusion.However,such a high level of TCM clinical research remains scarce,in recent years,the number of TCM research keep sustainedgrowth,buthigh-qualityevidence increased disproportionately,the main reason is the rigorous methodology design,so improving the level of clinical research design is the fundamental way to solvetheproblem.TCMCRPDwillconstantly update the data and monitor the latest international clinical researches of TCM so that TCMCRPD users could study the clinical trial protocols which are recognized by international experts and improve their theoreticalknowledgelevel.Thiswouldalso promote the further development of the TCM clinical research methodology,improve the design of the TCM clinical trials and ensure the quality of the TCM clinical trials.Finally,this would help to realize the proper and standard evaluation of the clinical efficacy and value of TCM.

Figure 2 The Technology Roadmap to Establish TCMCPD

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