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Clinical Studies and Randomized Controlled Trials in Chinese Herbal Medicine: A Historical and Contemporary Review - Part Two

by Zhaoxiang Bian and David Moher

Quality Control of Chinese Herbal Medicine

One of the basic requirements of RCTs is to standardize every element of the intervention, with a view to ensuring that every subject in a trial receives the intervention with the same quality and quantity, therefore preventing bias in the evaluation of its efficacy and safety. While it is difficult, if not impossible, for us to trace how quality control was conducted in ancient clinical studies, the situation in current clinical studies in the form of RCTs is not reassuring. Results from our previous study showed that only one trial mentioned quality control of herbs in 167 RCTs [26]. We do admit that difficulties in exercising quality control of CHM products in RCTs exist, and that the situation is completely different in RCTs in conventional medicine with pharmaceutical intervention, in which RCTs must follow guidelines set down by the International Conference on Harmonisation (ICH). These guidelines call for extensive quality control measures in studies approved by regulatory agencies (e.g., United States Food and Drug Administration [FDA]), where requirements for quality control on pharmacological interventions are described in detail in federal regulations known as current Good Manufacturing Practices (cGMPs) (e.g., 21 CFR 210) [27]. Critical considerations in quality control of pharmaceutical drugs are addressed, such as active ingredient identity, purity, potency, as well as final product sterility, stability, and numerous other criteria. Unfortunately, many aspects of quality control for CHM products used in clinical trials have been ignored. Generally, to date, practitioners of CHM have all along used raw medicinal plants to prepare customized treatments for their patients, and it is very difficult to standardize each customized treatment, which could perhaps explain why there has been little attention paid to the quality control of CHM in RCTs. It may be so in clinical practice, but we hasten to point out that in clinical study, if quality control for herbal intervention is lacking, it is impossible to ensure all participants take the same agent in terms of quality and quantity, and hence differences generated by the trial cannot reflect the true disparity on their efficacy for the targeted disease or syndrome. Therefore, standardization of the intervention of CHM must be emphasized to safeguard the basic quality of the clinical trials. A few key aspects, such as species of herbs, location of production, collection of herbs, processing method, as well as the screening for contamination of CHM products should be emphasized for the quality control.

There is no doubt that quality control of CHM for clinical trials is a complex issue. The first step should be to standardize the fundamental items of the herbs used in CHM, such as the exact species and subspecies, ideal growing locations, environmental conditions, harvesting methods, etc., to ensure the quality of the raw materials produced from the herbs. In the People’s Republic of China (PRC), the government has already implemented guidelines for the cultivation of CHM materials with reference to the origin of growth for over 70 medicinal plants in five major provinces [31]. The guidelines, the Good Agricultural Practice (GAP) for Chinese Crude Drugs, set down regulations for seed selection and storage, site selection for cultivation base, fertilizer application, water sources and usage, pesticides monitoring, harvesting practices including packaging, storage and field sanitation, etc. This is certainly a move in the right direction.

The second step will be to standardize the processing method for raw materials, because it may affect the function of herbs. It is believed that different processing methods, such as water, alcohol, acetone or combination extraction methods, affect the chemical structure or activity of the active compounds in herbs, though solid research in this area is lacking [28]. The need for this standardization is highlighted in the latest version of the Chinese Pharmacopoeia [32]. However, it covers only 75 commonly used CHM products containing materials processed from herbs. Action should be taken to develop standard operating procedures (SOPs) outlining specific steps to be followed during the processing of herbs and raw materials used in CHM.

The third step will be to standardize the preparation procedure of the final products, be they pills, tablets, powders, granules, oral liquids, teas, syrups, or capsules. This has already been applied to licensed herbal products, and the government of the PRC has implemented Good Manufacturing Practice (GMP) guidelines for CHM products on the mainland of China. These guidelines established basic national requirements for CHM products, from selection of raw materials to the quality control system of the final products. To ensure their relevance, validity, and authority, these GMP guidelines must be continually updated and kept current (cGMP). Without such guidelines and standardization of the preparation procedure of the final products used in RCTs of CHM, internal and external validity of the results from such studies will always be cast in doubt.

The fourth step will be control of contamination with heavy metals and pesticides in CHM products, which has always been a topical issue [29]. Such contamination does affect the quality of CHM products used in clinical trials and also the safety assessment of intervention in the trial. Common heavy metals including mercury, lead, arsenic, copper, and cadmium have the potential for acute and chronic toxicity depending on dosage and duration of exposure. As for pesticide contamination, this is the most dangerous to human health. Exposure to pesticide residues can result in many different adverse health consequences, from acute problems such as skin rashes and asthma attacks to chronic problems including emphysema and cancer [30]. Regulations must therefore be developed to minimize these contaminations.

The fifth step will be to evaluate qualitatively and/or quantitatively the quality of CHM based on biomarkers from herbs. To this end, it is necessary to determine most of the chemical constituents of herbs used in CHM in order to ensure the reliability and repeatability of pharmacological and clinical application, to understand the bioactivities and possible side effects of the active compounds, and to enhance product quality [33]. Hence, chemical profiles such as a chromatographic fingerprint of CHM or its product should be constructed and used as a reference by which quality of the CHM products can be measured. The combination of fingerprints from both raw herbal materials and the final products would be required to validate each step of the processing method. This processing, authentication, and identification of CHM materials and their products can be conducted even if the identity and/or content of the chemical characteristics of the constituents are not ascertained in the CHM materials. Unfortunately, no such steps have been taken, nor are there relevant guidelines in existence.

Taking the above-mentioned steps and developing such guidelines will be time-consuming endeavours that require the concerted efforts of numerous stakeholders including CHM practitioners, researchers, scientists, and policy makers from across the world. The ultimate goal of these guidelines—whether voluntary or mandatory—will be to standardize CHM interventions with stringent quality control measures to ensure their consistency and safe application in clinical trial.

Reporting Quality of RCTs in Chinese Herbal Medicine

Reporting of clinical trials is the only method for the vast majority of readers to understand how a study has been conducted and to understand its result, although some readers may have other channels to access the details of a particular trial. Readers of RCTs have a right to obtain better information about a trial so that they can understand and may apply the results into their practice. It is therefore imperative that the authors provide sufficient information in their published reports. Unfortunately, no reporting standards for RCTs in CHM exist at the moment. Reporting requirements for clinical trials in conventional medicine, on the other hand, have improved substantially since the 1960s, and one of the tangible outcomes of such improvement is the revised CONSORT (Consolidated Standards of Reporting Trials) checklist [34]. With the revised CONSORT checklist plus five specific items for CHM, our previous study, the reporting quality analysis about included RCTs in one SR published in the Cochrane Library, showed that most papers have not adequately reported all the details required of a study [35]. Detailed information is listed in Table 2.

SECTION/Topic

Description

N

Percentage %

TITLE

Identifies study as a RCT

3

5%

ABSTRACT

Has an abstract

36

55%


Has a structured format

23

35%


Gives hypothesis (or rationale)

0

0%


Gives number of patients

26

39%


States whether analysis was by intention-to-treat

0

0%


Gives method of randomization

0

0%


States results

36

55%

INTRODUCTION

Scientific background

36

55%


Explanation of rationale

18

27%

METHODS

Diagnostic criteria

58

88%


Inclusion criteria

23

35%


Exclusion criteria

12

18%


Informed consent form

3

5%


Ethic committee approval

3

5%


Settings and locations where the data were collected

37

56%

Intervention

Syndrome of disease based on CHM

30

45%


Rationale of CHM composition

66

100%


Composition of CHM formulas

57

86%


Preparation form of CHM

66

100%


Quality control of CHM

0

0%


Precise details of the interventions intended for each group

65

98%


States methods of administration

64

97%


States time of administration

62

94%


States duration of treatment

63

95%


States duration of follow-up

7

11%

Objectives

Specific objectives

64

97%


Hypothesis

0

0%

Outcomes

Defined primary outcome measures

65

98%


Defined secondary outcome measures

1

2%


Methods to enhance the quality of outcome measurements

3

5%

Sample size

Sample size

64

97%


States sample size calculation

1

2%


Explanation of any interim analyses

0

0%


Explanation of stopping rules

0

0%

Randomization

States method to generate the random allocation sequence

9

14%

Sequence generation

States whether sequence was concealed until interventions were assigned

0

0%

Randomization

Allocation concealment

States method to implement the random allocation sequence

1

2%

Randomization

Implementation

States who generated the allocation sequence

0

0%


Who enrolled participants

0

0%


Who assigned participants to their groups

0

0%

Blinding

States that the trial is blinded or open.

7

11%


Participants were blinded to group assignment

7

11%


Investigators were blinded to group assignment

4

6%


Assessors were blinded to group assignment

0

0%


States how the success of blinding was evaluated

0

0%

Statistical methods

Defines statistical methods

27

41%

RESULTS

Participant flow

Flow of participants through each stage

0

0%


Describes protocol deviations and reasons

1

2%

Recruitment

Dates defined periods of recruitment

20

30%

Baseline data

Baseline of clinical characteristics of each group

39

59%

Numbers analyzed

Actual number of participants in each group

65

98%


"intention-to-treat" analysis

1

2%


States withdrawal/ dropout

5

8%

Outcomes and estimation

Summary of results for each group with primary and secondary outcomes

66

100%


Estimates effect size

43

65%


Estimates precision of effect size ( 95% confidence interval)

0

0%

Ancillary analyses

Addresses multiplicity by reporting any other analyses performed including subgroup analyses and adjusted analyses

2

3%

Adverse events

States important adverse events or side effects

13

20%

DISCUSSION

Interpretation

Interpretation of results / states dangers associated with multiplicity of analyses and outcomes

0

0%


Interpretation of the results / states sources of potential bias

0

0%

Generalizability

Generalizability (external validity) of the trial findings

0

0%

Overall evidence

Interpretation of results in context of current evidence

66

100%


Table 2. Revised CONSORT checklist.

(This table was originally published in JICM 2006, 4, 233-242, cited with approval from the JICM.)

Recently, development of CONSORT guidelines for CHM trials have been initiated by some researchers [36], and it is hoped that the revised CONSORT checklist will become available in the near future. We strongly recommend that editors of CHM journals require authors to use a structured approach to presenting their trials as a condition of publication. Such requirement may induce investigators to organize their protocols at an early stage of their research with an eye toward publication. Use of flowcharts, checklists and standardized reporting format should enhance the quality of the contents as well as presentation of the reporting of RCTs of CHM.

Major Challenges for Randomized Controlled Trials in Chinese Herbal Medicine in the Future

Although case studies are still used in clinical trials in CHM today, more and more practitioners and researchers understand that the RCT is the golden standard to evaluate efficacy and safety of CHM for specific diseases. Many RCTs in CHM have been conducted in the past two to three decades [14], which followed the guidelines of RCTs. Although the quality of these RCTs is still relatively low, they can be improved if more attention is paid to the various aspects mentioned above. In addition, if RCT modalities can be modified for CHM, and if outcome assessments for CHM, such as those subjective aspects in TCM practice, including pulse-taking and tongue-observation can be improved, it is hopeful that the quality of RCTs in CHM can be substantially enhanced.

As discussed before, treatment based on symptom differentiation is the cornerstone of CHM practice. Treatment methods are adjusted according to the change of symptoms in the course of treatment, and different patients may be given different treatment methods. On the other hand, the steadfast rules of RCTs require that intervention should be kept identical in terms of quality and quantity throughout the entire trial period. Debates about RCTs in CHM arise from this inherent paradox between CHM practice and RCT requirements. Should the absolute essence of TCM be embraced, it would be impossible to conduct RCTs in it, and if the requirements of RCTs are abided by, it will violate the core nature of TCM. In view of such a paradox, RCTs in CHM tend to adopt a compromised approach—to regard CHM as a fixed and unchangeable intervention. That means that the formula of intervention, dosage of each herb and the whole product are fixed for the entire course of the trial. Undoubtedly, in these trials the theories of TCM have not been fully followed although the decision of which formula to take is based on symptom differentiation. It could be foreseen that this dilemma will last for a long time if no better solution can be found in the near future. In our opinion, it is important for researchers to understand what they want to approve in their trials. If the trial aims to test the efficacy of an herb or a formula toward a specific disease, it is necessary to keep the herb or formula fixed throughout the entire course of the trial. And as such, there is no violation to RCT protocols. If the trial aims to test the efficacy of an herb or a formula toward a specific syndrome, then undoubtedly interventions should be adjusted according to the change of syndromes. Otherwise, the results of clinical trials cannot represent the effect of intervention toward the syndrome. In sum, protocol for RCTs in CHM should accommodate considerable variations, especially in the course of treatment. Based on TCM theories, if modification of treatment methods is unavoidable while at the same time RCT requirements have to be met, the best way out is to test the efficacy of treatments with different formulae in terms of herbs and dosage during the course of treatment. In this way, requirements of both TCM and RCTs can be met. A diagram to this effect is shown in Figure 2.

Figure 2.How the requirements of both RCTs and TCM can be met.

As for outcome assessments in RCTs in CHM, emphasis should be given on index selection and the objective assessment of subjective aspects. Index selection should be based on objective outcomes of the trial. For example, if the aim of the trial is to evaluate the efficacy of an intervention against a certain syndrome, it is important to select indices that reflect micro changes such as those in the individual syndrome as well as macro changes such as the quality of life of the subject. If the target of the trial is the syndrome while the selected indices are toward the disease, it will not be able to reflect the efficacy of the intervention completely.

The assessment of subjective indications in clinical trials is a challenge for researchers. An example from conventional medicine may give us some hints as to how to find a proper solution to this critical problem. Irritable bowel syndrome (IBS) is a very common digestive disorder, which is characterized by abdominal discomfort or pain associated with defecation or a change in bowel habit and features of disordered defecation. No objective indications so far can be used to judge the efficacy of interventions for IBS. Global symptom improvement (GSI) at the end of the treatment course is selected as the primary endpoint, based on the suggestion of the Rome III Working Group [37]. Other indirectly related indications are used as secondary outcomes. Integrating GSI with the change of related symptoms is a current recommended method from the Rome III Working Group to judge the intervention’s effect toward IBS. This modality may provide an example for outcome assessment of CHM in clinical trials. Based on the aim of the trial, the primary outcome assessment could be fixed on the major targeted symptoms, and the secondary outcome assessment indices could focus on the related symptoms, thus coming together to assess the efficacy and safety of CHM.

Summary

Clinical research is a fundamental component in evidence-based medicine (EBM). Although the majority of clinical trials of CM in ancient times were in case study format, more and more RCTs in CHM have emerged recently. Though the quality of these RCTs is relatively poor at present, the situation would improve if more attention were paid to participant selection, randomization, allocation concealment, blinding, and quality control of CHM from raw materials to the final product, and reporting. CONSORT for TCM is expected to have possible contributions to improving the quality of reporting on CHM. Besides these factors, proper methods should be found to solve the dilemma between the inherent requirements of RCT and CHM. As regards outcome assessment, more attention should be paid to index selection and assessment of subjective indications.

Contact Details

Zhaoxiang Bian, PhD

Associate Professor

School of Chinese Medicine

Hong Kong Baptist University

Kowloon Tong, Hong Kong

bzxiang@hkbu.edu.hk

This review is based on our previous four papers published in Zhong xi yi jie he xue bao, 2006. We thank the journal for permitting us to conduct this review based on these four papers and the cited tables therein. Edited by Michael McCarthy, Stephen Birch, et. al. (eds.), Thieme Almanac 2008: Acupuncture and Chinese Medicine, Thieme: Stuttgart–New York; 2008.

References

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27. Code of Federal Regulations, Title 21, Volume 4, Part 210, Revised April 1, 2005.

http://www.gpoaccess.gov/cfr/index.html

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31. Good Agricultural Practice for Chinese Crude Drugs, State Food and Drug administration, http://www.sfda.gov.cn

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35. Bian ZX, Moher D, Dagenais S, Li YP, Wu TX, Liu L, Miao JX, Song L, Zhang HM. Improving the quality of randomized controlled trials in Chinese herbal medicine, part IV: applying a revised CONSORT checklist to measure reporting quality. Zhong Xi Yi Jie He Xue Bao. 2006;4(3):233-42.

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