Three subjects on ethics concerning the manner or principles of scientists or investigators are discussed on this paper. There are two different guidelines for clinical research and epidemiological research in Japan, however, both of them are similar and overlap in many points; I believe the two guidelines should be integrated into one guideline. For clinical trials, investigators should take a training course, and the clinical trials should be registered prior to the initiation of the trial. Insurance for clinical trials should also be developed for investigators, equal to the insurance for pharmaceutical companies.
I would like to emphasize that it is not sufficient to merely prepare a guideline, rather it is the establishment of volunteers' rights and consideration of investigators' manner are the most important factors for research. Informed consent is translated “explanation and agreement”, however I believe this translation is not sufficient, because the volunteers may give consent without a full understanding of the clinical trial. Paternalism in clinical research is not proper and there are some investigators who do not understand the importance of informed consent. There are four kinds of manners in clinical research. The first is a humble attitude of the investigators and they should be aware that their clinical research may harm the volunteers. The second factor is to pay attention to the hope or desire of the volunteers. The third is to maintain confidentiality of the personal information such as name, telephone number, address or e-mail in the proper manner. Pictures and videos of the volunteers or patients are also included as personal information. The personal information should not be open to the public, except for a request from the ethics committee or the court. Concerning the ethics committee, I do not think it is essential for the committee to have some members from outside. On investigators principles, I have discussed some examples of improper performance of scientists such as fabrication, manipulation and plagiarism. The best means to avoid such improper performance is to keep the atmosphere of research or laboratories balanced, so as not to tempt scientists or investigators into wrongful behavior, improper discipline or excessive competition.

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Much attention has been focused on translating basic research more quickly into human studies, tests and treatments that can improve clinical practice. Therefore, in order to solve the problem of clinical setting for the maximum benefit of patients, it is necessary to improve not only bench to bedside research, but also that of bedside to practice. Japan has traditionally been a strong base for basic research in the areas of medicine, pharmacy, science and technology. However, the output of clinical research has been regrettably low with a significant gap between basic and clinical research activity. Under the present circumstances in Japan, there seem to be many obstacles for physicians who are engaged in clinical research. To improve this situation, the Japanese government has set a 5-year plan to boost clinical research by increasing the budget for research and devising development programs to promote clinical research. Various plans have been proposed, and some plans have already been implemented by the government, academia and industry. To build a competitive environment for clinical trials, it is necessary to advance these activities through infrastructure development, human resource development, and the appropriate injection of public funds in the near future. Here, we present various measures to promote clinical trials in Japan and overseas.

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Many physicians do not have the opportunity to obtain fundamental knowledge concerning a drug evaluation. Therefore, although the number of clinical trials including multinational studies is recently increasing in Japan, the quality of these trials is sometimes relatively poor. To improve this situation, a Council of Certified Physicians for Clinical Trials will be founded in the near future. The council will develop a sample of educational programs, monitor the ongoing programs of each academic society and provide the opportunity for physicians to be fully informed regarding clinical trials and drug evaluations. Finally, the council will certify physicians who have sufficient pertinent knowledge to carry out clinical trials.

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The placebo effect can be observed in various medical conditions, and has been documented by randomized placebo-controlled drug studies. One of the best examples is the placebo effect in Parkinson's disease (PD). The placebo effect is observable not only in drug trials but also with surgical therapies, such as deep brain stimulation, fetal tissue transplantation, and infusion therapy of a neurotrophic factor. A recent study using positron emission tomography (PET) with raclopride demonstrated that the release of endogeneous dopamine in the dorsal striatum mediates the placebo effect in PD, suggesting that the placebo effectiveness is achieved by endogenous dopamine supplementation. Although the detailed pathophysiological mechanism underlying the placebo effect is unclear, the placebo effect has been explained by two mechanisms: the conditioning theory (pavlovian conditioning) and the cognitive or expectancy theory (expectation of clinical improvement). Speculatively, it may be that the placebo effect in PD is related more to cognitive mechanisms. Numerous studies have suggested a functional relationship between dopamine and the reward system. Understanding the placebo effect is important for designing clinical trials and interpreting their results.

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Monetary incentives for clinical trials may have only a limited incentive value to promote clinical trials in Japan. The data of clinical trials should be published in Japan. A publication committee, made up of representatives of academic and other institutions participating in the study or other recognized leaders in the field, should be organized before the start of the trial. The publication committee would serve as an independent body of scientific and medical experts. Authorship of the publication should also be considered to belong to the doctors. All publications (e. g., original manuscripts and abstracts of data and information related to the clinical study) will be submitted in advance to the Publication Committee for review according to the procedure. These policies of publication will encourage many Japanese doctors to participate in clinical trials.

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Item 2 of the new, 5-year action plan to revitalize clinical trials comprises ‘fostering and securing personnel to conduct clinical trials and research’ . Accordingly, the fostering and securing of clinical research coordinators, biostatisticians and data managers are being promoted comparatively proactively; however, the situation regarding doctors remains unsatisfactory. Herein, we introduce initiatives taken by Ehime University Hospital to tackle this. Ehime University has constructed 1)an internal hospital medical team based on inter-departmental collaboration within the University Hospital to conduct identical clinical trials, and 2)a clinical trial medical group including local institutions, as a way of creating an internationally competitive structure. The process of creating this structure makes it possible to find doctors to proactively conduct clinical trials.
The results of an attitude survey conducted to assist with creating an environment to foster doctor involvement revealed that 1)few doctors thought it would increase their self-evaluation, 2)many doctors were not using their research budgets, and 3)many doctors thought that clinical trials take time and effort and so did not want to conduct them. In accordance with these requests, we introduce initiatives already undertaken to improve the image surrounding clinical trials. Our goal is to further promote the creation of an environment that motivates doctors to conduct clinical trials.

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Health food products or supplements are expected to promote health and to prevent and treat diseases; consequently their use has recently increased. Therefore, it is necessary to accurately and efficiently examine adverse events associated with them. Many algorithms for the evaluation and classification of causal relationships of adverse events related to medications have been proposed, however, there is no algorithm concerning health food products or supplements. In this study, considering these circumstances, we designed algorithms for the evaluation and classification of causal relationships of adverse events with health food products or supplements and evaluated their reliability. The algorithms previously proposed for the evaluation and classification of causal relationships of adverse events with medication (Naranjo CA, et al . Clin Pharmacol Ther 1981; 30: 239-45, Jones JK. Fam Community Health 1982; 5: 58-67) were modified for the present study. We assessed the effects of the ginkgo biloba extract, a common health food supplement, and reviewed the literature using databases such as MEDLINE. We found 29 cases of adverse events related to intake of ginkgo biloba extracts. Using the modified algorithms, the causal relationship of ginkgo biloba extracts with adverse events in the cases was independently evaluated by 4 raters (a clinician and 3 pharmacists), and the inter-rater reliability was tested. The coefficient of intra-class correlation calculated by the total score of Naranjo et al . was 0.65 and the 95% confidence interval was [0.48, 0.79]. The κ coefficient of multi-rater reliability was 0.27 in the algorithm of Naranjo et al., while it was, 0.26 when 5 studies were excluded using the algorithm of Jones. In conclusion, the modified algorithm of Naranjo et al. may be recommended for evaluating causal relationships of adverse events with health food products or supplement consumption.

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