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  6. 6. Relation to other projects

6. Relation to other projects

The relation of this project to some other projects is described below.

(1) Scope

The research questions in controlled trials involve interventions and controls. This report includes a few studies comparing Kampo medicines, using several Kampo medicine groups as intervention or evaluating the system of Kampo medicine itself.

Further studies of this kind using Kampo formulations are desired.

In Kampo medicine in Japan, not only Kampo formulations but also decoctions are sometimes used. RCTs using decoctions are expected in future, but were listed as excluded references in this report. When a certain number of references are accumulated, their structured abstracts will be prepared.

For RCTs of crude drug therapies not based on Kampo formulae, preparation of structured abstracts and accessible forms of providing them are desired. Cooperation with other related organizations will also be a future challenge.

Although not limited to traditional medicine, the Japanese website Minds (http://minds.jcqhc.or.jp/) has prepared and published free of charge Japanese translations of SAs in the Cochrane Library that are related to the Japanese treatment guidelines published on the Minds website. The Cochrane Library anticipated giving access to its abstracts in English, Spanish, Portuguese, Italian, Croatian, and Chinese, as well as Japanese by the end of 2013. Minds has also prepared Minds abstracts and published them on the website previously.

(2) Development in Japan and Korea of universal-style structured abstracts of RCTs in the fields of traditional medicine and complementary and alternative medicine

The first initiative to deliver SAs to people who require them was the ACP Journal Club in 1991. A further, similar initiative was taken by the Evidence-Based Medicine.

In the field of complementary and alternative medicine (CAM), there is the quarterly journal FACT (Focus on Alternative and Complementary Therapies) first published in 1996. Before long, an initiative was born in 2001 for Japanese translations on acupuncture, which have been serialized in the journal Ido no Nippon (the Japanese Journal of Acupuncture & Manual Therapies), and a collection of all 50 translations since 1996 has been published as a book by Ido no Nipponsha as Hari no Ebidensu (Evidence for Acupuncture (provisionally translated title). Further Japanese translations followed with each edition of Ido no Nippon (the Japanese Journal of Acupuncture & Manual Therapies) featuring translations, and with the cumulative total reaching 150, an enlarged and revised edition was published in 2009 with comments by Japanese.

Several other initiatives have followed in Japan that are modeled on EKAT.

First, in 2009, a research group within the Association for Health Economics Research and Social Insurance and Welfare (ASIW), called the Food for Special Dietary Uses and Nutrition Therapy Research Group (headed by Kiichiro Tsutani), published the "Tokubetsuyotoshokuhin oyobi Eiyoryoho no Ebidensuto ni Kansuru Joho no Syusyuseirigyomu: Heisei 20 Nendo Hokokusho" (Evidence Reports of Food for Special Dietary Uses [FSDU] and Nutrition Therapy 2008] (http://www.shafuku.jp/healthfood/pdf/report.pdf) (in Japanese).

Then in 2012, a Ministry of Health, Labour and Welfare (MHLW) scientific research grant entitled "Higashi Ajia Dento Igaku no Yukosei, Anzensei, Keizaisei no Shisutematic Rebu" (Systematic Review of the Effectiveness, Safety, and Economy of East Asian Traditional Medicine [Principal Researcher: Kiichiro Tsutani]) prepared a report entitled "Shinkyu Ebidensu Repoto 2011" (Evidence Reports of Japanse Acupuncture and Moxibustion 2011), "Anma Massagi Shiatsu (Amashi) Ebidensu Reporo 2011" (Evidence Reports of Anma-Massage-Shiatsu 2011), and "Kampoyaku no Keizaihyoukaryoiki no Ebidensu Repoto 2011" (Evidence Report of Economic Evaluation of Kampo Treatment 2011). The details are summarized below.

The researchers found 421 papers after searching Ichushi Web Ver. 4, The Cochrane Library (CENTRAL), the Japanese Acupuncture and Moxibustion RCT Database (JAC-RCT) by Tsutani and Suyama, the Acupuncture Clinical Trial Paper List (provisional name: JSAM-RDB) edited by members of the Japan Society of Acupuncture and Moxibustion, as well as a partly hand search of RCT papers. Subsequent screening found 53 papers meeting the selection criteria for which SAs were prepared. With third-party neutral comments, those SAs were compiled as “Nihon Shinkyu Ebidensu Repoto 2011 – 53 no RCT – (EJAM 2011)”. An English version was also prepared as “Evidence Reports of Japanese Acupuncture and Moxibustion 2011: 53 Randomized Controlled Trials (EJAM 2011)”.

In the field of Amashi, RCT papers were exhaustively gathered using Ichushi Web Ver. 4. SAs were prepared for 18 (19 papers) out of the 105 that fitted the criteria and these were compiled as Anma-Massaji-Shiatsu Ebidensu Repoto 2011 – 18 no RCT (EAMS 2011). An English version was also prepared: Evidence Reports of Anma-Massage-Shiatsu 2011: 18 Randomized Controlled Trials of Japan (EAMS 2011).

For the economic evaluation of Kampo medicines, a search was performed using Ichushi Web Ver. 5. After screening, 10 papers were identified as economic evaluations of Kampo medicines. SAs were prepared for these and were compiled as Kampo Chiryo no Keizai Hyoka Ebidensu Repoto (Evidence Report of Economic Evaluation of Kampo Treatment: [EREK] 2011).

In Korea, the Special Committee for EBM of the Korean Oriental Medicine Society (KOMS), with which JSOM has established an exchange agreement in 2009, published the Korean translation (근거중심의 한방처방:임상 근거를 만들고, 전달하며, 사용하는) of Evidence Reports of Kampo Treatment 2010: 345 Randomized Controlled Trials (EKAT 2010) on 15 July 2011.

The Committee also used the same methods as for EKAT to prepare an evidence report on traditional Korean medicine, which was published on 20 January 2012 as근거중심의 한의치료. The Committee prepared SAs in Korean after gathering and selecting 306 papers (including 134 RCTs), which include trials using designs other than RCT designs and were found by searching The Cochrane Library (CENTRAL), PubMed, the Korea Institute of Oriental Medicine (KIOM) database, and the websites of 17 sub-committees in the field of traditional Korean medicine. The SAs for the 134 RCTs were translated into English in “Heisei 22-23 nendo Kosei Rodo Kagakukenkyu Chiikiiryo Kibankaihatsu Suishin Kenkyujigyo -Higashiajia Dentoigaku no Yukosei Anzensei Keizaisei no Shisutematikku Rebyu” (Systematic Review of the Effectiveness, Safety, and Economy of East Asian Traditional Medicine, a Research on Region Medical under the 2010/2011 Ministry of Health, Labour and Welfare Scientific Research grants) (Principal Researcher: Kiichiro Tsutani). The report is entitled “Evidence Reports of Korean Medicine Treatment 2010: 132 Randomized Clinical Trials (EKOM 2010)”. This evidence report contains 77 RCTs on acupuncture and moxibustion, 27 RCTS on herbal medicines, one RCT on both, and 27 RCTs on other traditional Korean medicine.

Of the above, SAs on Japanese acupuncture and moxibustion (in Japanese and English), Amashi (Japanese and English), traditional Korean medicine (English), economic evaluation of Kampo treatment (Japanese) can be accessed on the “Higashi Ajia Dento Igaku Ebidensu Repoto” (Evidence Reports of Traditional East Asian Medicine: ETEAM) website, which is searchable at http://jhes.umin.ac.jp/team.html. The website also has links to the EKATs.

(3) CONSORT Statement

With the aim of improving the quality of references of RCTs, the CONSORT statement was published in 1996 and revised in 2001 and 2010 (http://www.consort-statement.org/).

The 2010 version consists of a total of 25 items, and authors are requested to attach a checklist showing on which page the information on each item can be found. They are also requested to attach a flowchart representing subject disposition in case results might differ depending on the analysis population. These requirements not only control the quality of RCT articles but also improve the quality RCT themselves. The JSOM has added the statement that “RCT papers shall conform to revised CONSORT statement (2001)” to the instructions to authors its March 2008 revision (Nihon Toyo Igaku Zasshi [Kampo Medicine] 2008; 59: 580-89). Currently CONSORT statement 2010 is required to use.

Two herbal extensions of the CONSORT statement have been published:

Gagnier JJ, Boon H, Rochon P, Moher D, Barnes J, et al. Reporting randomized controlled trials of herbal interventions: An elaborated CONSORT statement. Annals of Internal Medicine 2006; 144(5): 364-7. (Available in Japanese: Okabe T, Tsutani K [trans], Habu kainyu no randamuka hikakusiken hokoku: shosai na CONSORT seimei. In: Nakayama T, Tsutani K [supervise-eds] Rinshokenkyu to Ekigakukenkyu notameno Kokusairuru-shu (International Rulebook for Clinical and Epidemiological Studies. Tokyo: Life Science Publishing Co., Ltd.; 2008: 156-63)

Bian ZX, Moher D, Dagenais S, Li YP, Wu TX, et al. Improving the quality of randomized controlled trials in Chinese herbal medicine, Part IV: applying a revised CONSORT checklist to measure reporting quality. Journal of Chinese Integrative Medicine (Zhong Xi Yi Jie He Xue Bao) 2006; 4(3): 233-42. (Available in Japanese: Tsutani K, Araki S [trans]. Chuyaku no randamuka Hikakushiken no Hokoku ni kansuru CONSORT seimei. In: Nakayama T, Tsutani K [supervise-eds], Rinshokenkyu to Ekigakukenkyu notameno Kokusairuru-shu [International Rulebook for Clinical and Epidemiological Studies]. Tokyo: Life Science Publishing Co., Ltd.; 2008: 164-9).

The former applies to plain herbs, while the latter to Chinese prescriptions. The former provides detailed explanation on how to describe “intervention” in consideration of the nature of crude drugs, and the latter gives consideration to the diagnosis system of Chinese traditional medicine and years of clinical experience.

In the third phase of the Special Committee for EBM starting 2009, the Task Force for KCONSORT (KC-TF) was established. A survey of the references compiled as structured abstracts in EKAT 2009 for compliance with the CONSORT statement demonstrated that few were good in quality. Particularly, the following defects were commonly noted: no indication that the study is an RCT in title/abstract; no indication of the study site or period; no indication of the name of the manufacturer of Kampo formulation or the daily dosing frequency; no indication of the methods and assurance of randomization; unclear numbers of enrolled patients, assigned patients, and analyzed patients; no indication of adverse events in the control group. In the future, Kampo RCTs will also be required to be reported in compliance with the CONSORT statement. These findings were presented in the following meeting and published in Nihon Toyo Igaku Zasshi (Kampo Medicine) as study results.

Okabe T, Arai I, Tsutani K. Ebidensu repoto purojekuto: autorain to Kampo RCT no shitsu hyoka (Evidence Report Project [1] Outline and evaluation of Kampo RCTs). The Japan Society for Oriental Medicine 60th Annual Meeting Forum “Kampo no ebidensu wo tsutaeru (Transfer Kampo evidence),” 21 Jun. 2009, Tokyo. Nihon Toyo Igaku Zasshi (Kampo Medicine) 2009; 60 suppl.: 160 (in Japanese).

While it is recommended that RCTs be published in accordance with the CONSORT statement, the existing CONSORT statement and its extensions made it clear that it was not possible to correctly describe Kampo formulation interventions. To resolve that problem and to enable completion of the necessary information in the RCT paper methods field without needing to have a high degree of familiarity with Kampo formulations, the KCONSORT webpage was published in English in August 2011 by the Department of Pharmacognosy, Phytochemistry and Narcotics (DPPN), National Institute of Health Sciences (NIHS) of Japan, and the Research Center for Medicinal Plant Resources (RCMPR), National Institute of Biomedical Innovation (NIBIO) of Japan (http://plaza.umin.ac.jp/~kconsort/) under work collaboration of KC-TF and Japan Kampo Medicines Manufacturers Association (JKMA). The website is intended to replace the need for authors writing RCTs on Kampo preparations to complete detailed information in their papers relating to the Kampo preparations used in research, by including the web address of this website, which contains detailed information on Kampo preparations.

The CONSORT statement was extended to include various study designs such as epidemiological studies and systematic reviews, and further studies on above-mentioned complementary and alternative medicine (CAM). In this context, the “Equator Network” was established in June 2008 to cover the publication guidelines for all these studies for enhanced accessibility and to help prepare such guidelines in future [http://www.equator-network.org ].

The Japanese version of these guidelines are included in the following:

Nakayama T, Tsutani K (eds). Rinsho kenkyu to ekigaku kenkyu notameno kokusai ruru-shu (International Rulebook for Clinical and Epidemiological Studies). Tokyo: Life Science Publishing Co., Ltd.; 2008 (in Japanese).

(4) Clinical trial registry

In the Declaration of Helsinki revised in October 2008, a sentence “Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject” was added in section 19. However, this requirement is not well known. Therefore, the discussion here includes the historical background underlying the implementation of this requirement.

Awareness of the clinical trial registry (CTR) has increased since the 1990s, when evidence-based medicine (EBM) emerged. In particular, the problems became clearer after the Cochrane Collaboration, which plays a role in the EBM information infrastructure, was established in 1992 to fully implement systematic review (SR). SR is almost synonymous with meta-analysis (MA).

However, no matter how exhaustive the survey or search, how careful the assessment of quality, and how sophisticated the statistical method used for data consolidation, a problem of bias ("publication bias") arises when studies are not reported. This leads to flaws in decision making by health care providers, policy makers, medical consumers, etc. As a result, ineffective therapies, hazardous therapies, and therapies with poor cost-effectiveness are “used”.

Table 5 gives an example of publication bias in the area of acupuncture. Search for papers with an abstract published between 1966 and 1995 by the Medline identified 108 of 109 papers published in China (99%) that have shown favorable results, that is, demonstrated the efficacy of acupuncture compared with control. The efficacy rate was 75% in England and similar to that in China in other countries including Japan. This has been attributed to failure to publish studies that do not show efficacy.

Table 5

This situation was widely acknowledged by those involved in systematic review of these studies. Although some measures might avoid this bias, such as encouraging researchers to publish all studies, passing legislation mandating registry of all trials, and establishing a website to register planned or ongoing clinical trials, no specific measures were fully established.

In 2003, the National Library of Medicine (NLM) of the National Institutes of Health (NIH) established "Clinical Trials.gov" (http://clinicaltrials.gov/ct2/info/about) with the aim of encouraging patients to access information on clinical trials of new drugs (therapies) intended for life-threatening disease. This is also an aim of the 1997 US-FDA Modernization Act. This system was not intended to avoid publication bias, but partially did a limited number of diseases including cancer, AIDS, and Alzheimer's disease.

The Glaxo SmithKline fraud scandal reported on the front page of the New York Times dated 3 June 2004 triggered a worldwide reaction. In a clinical trial of an anti-depressant in children, the company failed to properly report attempted suicide as an adverse event. The scandal prompted worldwide support for legislation requiring clinical trial registration and raised ethical issues such as the risk adverse events in similar clinical trials and abuse of the altruistic goodwill of participants.

In September 2004, the International Committee of Medical Journal Editors (ICMJE) issued a statement that no manuscript would be accepted in advance of registration of the clinical trial. Trials already in progress were given additional time to comply. The Cochran Colloquium in October 2004 issued the "Ottawa Statement." The WHO also supported these statements by holding the “WHO Technical Consultation on Clinical Trial Registration Standard Meeting” in its headquarters in Geneva in April 2005 to determine 20 items to be registered, etc.

This trend continued between 2004 and 2005 as indicated below:

(1) Rinshoshiken no toroku to kekka no kokai (Clinical trial registry and publication of the results [regardless of whether or not results are positive or negative]). The 25th Annual Meeting of the Japanese Society of Clinical Pharmacology and Therapeutics Symposium 12 (18 Sept. 2004, Shizuoka). Rinsho Iyaku (Journal of Clinical Therapeutics Medicine) 2005; 21(1): 3-62 (in Japanese).

(2) Rinshoshiken toroku nikansuru “Otawa seimei” to “Junebu kaigi” no doko (“Trend toward clinical trial registry as advocated by the "Ottawa Statement" and "Geneva Conference."). Yakuri to Chiryo (Japanese Pharmacology & Therapeutics) 2005; 33(6): 543-66 (in Japanese).
   http://www.lifescience.co.jp/yk/jpt_online/ottawa/index_ottawa.html

(3) UMIN Clinical Trial Registry System Symposium (2 Feb. 2005)
   http://www.umin.ac.jp/ctr/symposium20050202.htm

In Japan, the University hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) (June 2005-), the Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC-CTI) (July 2005-), and Japan Medical Association Center for Clinical Trials (JMA CCT) system (December 2005-) were launched. Subsequently, the Japan Primary Registries Network (JPRN) (October 2008-) of the National Health Science Institute consolidated these three systems.

In 2007, the WHO established the International Clinical Trials Registry Platform (ICTRP, http://www.who.int/ictrp/en/) and opened a search portal (http://apps.who.int/
trialsearch/ ) to facilitate access to all systems worldwide for searching

Currently this site can be used to search for all registered trials, including trials of Kampo formulations in Japan.

In April 2007, interventional clinical studies supported by Health and Labour Sciences Research Grants were required to be registered. Also, in April 2009, the Ministry of Health, Labour, and Welfare “Ethical Guidelines for Clinical Research” required registry.

The intent of clinical trial registry has been discussed above from a historical perspective in some detail. Questions remain: how many RCTs and clinical studies are performed and what percentage of them is registered in Japan?

In a book summarizing the situation in various nations in the world released in 2006, it was estimated that 400 RCTs and 2,300 other clinical researches, for a total of 2,700, were performed at that time.

Matsuba H, Kiuchi T, Tsutani K, Uchida E, Ohashi Y. The Japanese perspective on registries and a review of clinical trial process in Japan. In: Foote M ed. Clinical trial registries: A practical guide for sponsors and researchers of medicinal product. Basel: Brikhäuser, 2006

According to the book, as of February 2006, the three systems combined had a total of 550 registries. UMIN-CTR was the first system in Japan, started in June 2005. A review in May 2010 found that the number of registries in 2006 was 259, 138 and 7 registries in UMIN-CTR, JAPIC-CTI and JMACCT, respectively. The total of 404 registries represented approx. 15% of all clinical studies (404/2,700).

A review showed that the number of registries in 2009 had risen to 1,311, 295 and 9, respectively, for a total of 1,615. Assuming that the number of clinical studies remained the same in 2009, i.e., approx. 2,700, registered studies accounted for approx. 60% (1,615/2,700) of all clinical studies.

The problem of publication bias was described above, citing the field of acupuncture in the period from 1966 to 1995 as an example. Is there currently publication bias in the reporting of studies on Kampo formulations?

Preliminary analysis of all 345 papers in EKAT 2010 revealed “favoring test treatment” results in 301 out of 308 trials (98%) (excluding those trials comparing only Kampo formulations with other Kampo formulation(s) as control). This result is consistent with the above-mentioned rate of publication bias in the reporting of acupuncture studies. In Japan, inasmuch as the percentage of registered clinical trials is increasing, it is hoped that clinical trials of Kampo formulations are also being registered so as to provide true efficacy and safety evidence.

The global trend is toward requiring not only registry of ongoing clinical trials but also publication of the results. NIH-funded trials must fulfill these requirements. The situation relating to the publication of results from trials of Kampo formulations registered in Japan is described in the following article:

Arai I, Tsutani K. Kampoyaku no rinshoshikentoroku to kekka no kohyojokyo (Situation of registry of clinical trials of Kampo medicine and publication of the results). The Japan Society for Oriental Medicine 61st Annual Meeting (5 Jun. 2010, Nagoya), Nihon Toyo Igaku Zasshi [Kampo Medicine] 2010; 61 suppl.: 244 (in Japanese).

Publication bias is considered to be more of a problem in CAM in broad sense than in conventional allopathic medicine. This is because CAM studies lack a regulatory framework, as many of these studies are conducted by physicians who are unfamiliar with clinical trial registry trends worldwide, including Japan. This is in contrast to clinical trials conducted by pharmaceutical companies.

The intent of this “Evidence Report” project, involving compilation of structured abstracts with third party’s neutral comments about RCTs in Japan, is to “tsutaeru (transfer)” users. Reducing bias is always considered as high priority in whole works of the project. However, publication bias cannot be prevented if the results of RCTs are not published.

We strongly recommend registration of all RCTs of Kampo formulations in Japan.

Furthermore, systems that allow for guarantees of quality and secondary analysis by accessing the raw data of clinical trials have been starting up since 2010 in the West and in Japan, and these should be extended to the field of CAM.

(5) The Cochrane Library (CENTRAL)

The Cochrane Library (CENTRAL) is a global RCT database platform, but includes only 67 of the 345 RCTs on Kampo formulations in EKAT 2010. The Center for Integrative Medicine, University of Maryland Medical School manages the compilation of RCTs on complementary therapies in CENTRAL. We have made contact with the Center and negotiated for the RCT papers compiled in EKAT to be added to CENTRAL. As a result, the Kampo RCT papers in EKAT 2010 will be included in CENTRAL, and it will have links to the English versions of JSOM’s EKAT SAs. When CENTRAL was updated in October 2011, additional EKAT papers were included. However, due to copyright issues, there are no links from the RCT papers on Kampo formulations that were originally included in CENTRAL. In any event, it is now possible to access all the Kampo formulation RCTs from the Cochrane Library (CENTRAL). When evidence-based clinical practice guidelines (CPG) are produced, CENTRAL will be used most often to search for RCT papers. It is expected that this will facilitate Kampo formulation RCT searches, and that there will be no gaps in the evaluation of Kampo formulations for such CPGs.

The following paper describes the above in detail.

Wieland LS, Manheimer E, Sampson M, et al. Bibliometric and content analysis of the Cochrane Complementary Medicine Field specialized register of controlled trials. Systematic Reviews 2013, 2: 51 (http://www.systematicreviewsjournal.com/content/2/1/51

(6) Clinical practice guidelines

Traditional medicines are already international commodities. From this perspective, Japan’s Kampo formulations have fallen a little behind. If high quality SAs are prepared for Chinese and Korean traditional medicines, then it may become possible to reduce confusion in the debate through the publication of clinical practice guidelines (CPG) for traditional medicines, something that the WHO Office for the Western Pacific (WPRO) attempted to do in 2005 and 2006.

Motoo Y, Arai I, Hyodo I, Tsutani K. Current status of Kampo (Japanese herbal) medicines in Japanese clinical practice guidelines. Complementary Therapies in Medicine 2009; 17: 147-54.

Motoo Y, Tsutani K. Dento Igaku no Gurobaru Shinryo Gaidorain wa Kano ka? (Is it Possible to Realize Global Clinical Guidelines for Traditional Medicines?) Nihon Toyo Igaku Zasshi [Kampo Medicine] 2006; 57 (4): 465-75 (in Japanese).

Furthermore, the WHO/WPRO traditional medicine CPG project was discontinued at the 5th meeting in Hong Kong (2007) due to strong opposition from Japan and others. However, work was continued in China and the following three volumes were published in 2011.

China Academy of Chinese Medical Sciences ed. Chinese medicine evidence-based clinical practice guidelines: TCM Internal Medicine (Chinese Edition) (中医循証臨床実践指南 - 中医内科). Beijing. China Press of Traditional Chinese Medicine, 2011

China Academy of Chinese Medical Sciences ed. Chinese medicine evidence-based clinical practice guidelines: Special disease (Chinese Edition) (中医循証臨床実践指南 - 専科専病), Beijing. China Press of Traditional Chinese Medicine, 2011

China Academy of Chinese Medical Sciences ed. Chinese medicine evidence-based clinical practice guidelines: Acupuncture (Chinese Edition) (中医循証臨床実践指南 -鍼灸). Beijing. China Press of Traditional Chinese Medicine, 2011

The following paper includes details of the above.

Yanagawa T, Tsutani K. Chuyaku no Kokusaika to Hyojunka ni Kansuru Chugoku no Seisaku. Dai 5 kai Chui Shinryo ni Kansuru Gyokai Hyojun to Shinryo Gaidorain. (Chinese Policies on Internationalization and Standardization of Chinese Medicines. 5th Industry Standard and Clinical Practice Guidelines for Traditional Chinese Medicine Therapy) Wakan’yaku 2013; No.720: 3-10 (in Japanese).

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