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Masaya GOTO and Atsushi ARUGA
Cooperative Major in Advanced Biomedical Sciences，
Joint Graduate School of Tokyo Women's Medical University and Waseda University (Accepted March 19， 2015)
The J apanese government encourages clinical trials accordingtothe“N ew 5 Yearly Clinical Trial Activation Plan." Investigator-initiated clinical trials in J apan could be improved. Some researchers believe they require more support to achieve higher quality. However， not enough data are available to discuss the level of support needed. We performed a check of medical school websites to determine how much support investigators receive. J apan has 80 medical schools， all of which have sponsor-initiated clinical trial support centers. Of the 80 cen -ter websites， 52 contain descriptions of investigator-initiated clinical trial suppor.tWe were not able to access the sections of 2 of the 80 websites that seemed to offer support information. All centers provide support information about sponsor-initiated clinical trials. Of 51 public schools， 36 mention investigator-initiated clinical trial support， and it is also mentioned by 16 of 29 private schools. We expected that the sponsor-initiated clinical trial support centers of the 80 medical schools may also provide support for investigator-initiated clinical trials. Not all schools mention investigator-initiated clinical trial suppor.tWe plan to mail a survey to those centers. Key W ords: investigator-initiated clinical trials， suppor，twebsite Iniroduction
The J apanese government encourages clinical tri -als with the healthcare policy known as the“New5 Yearly Clinical Trial Activation Plan"1).Clinical tri
-als in J apan have room to improve compared to ad -vanced nations2
). In one case， Novartis faces a possi
-ble criminal inquiry regarding the Diovan③ clinical tria.lWe must determine how to manage position -ing and compliance to avoid such inquiry activity. Some say stricter regulations regarding clinical tri -als are necessary3).We also have some protocols through which we could improve trial quality. Pro -tocols are quite important in ensuring the quality of clinical trial plans4
).In 2013， we checked the quality
of 113 investigator-initiated clinical trial protocols in the University of Tokyo Hospital and found many
fixable weak points according to SPIRIT 20135
) and determined that clinical trials required additional support.The SCIENCE COUNCIL OF J AP AN has stated that medical institutions and hospitals should aid investigator-initiated clinical trials and do more to manage them 6).Some suggest that we should
make the regulation more stringent; others worry that doing so might decrease the number of clinical trials and increase the human cost for manage-menf)8). Though such discussion has warmed up， we have insufficient data about investigator -initiated clinical trial support.We are only aware of a few case reports about a particular hospita19 )， some suggestions within the discussion10). Some data are available about sponsor-initiated clinical tri -als11)， but we cannot extrapolate data about 図 :Masaya GOTO Cooperative Major in Advanced Biomedical Sciences， Joint Graduate School of Tokyo Women's Medi -cal University and Waseda University， 8-1 Kawada-cho， Shinjuku-ku， Tokyo， 162-8666 Japan E-mail: [email protected]
Table 1 Support description difference between pub1ic schoo1s and private schoo1s Public Private Total Support discripiton 36 (71%) 16 (55%) 52 (65%) No support discription 14 (27%) 12 (41%) 26 (33%) Closed websites 1 ( 2%) 1 ( 3%) 2 (2%) Total 51 29 80 investigator-initiated clinical trials from them. The information is extremely limited and inaccurate. We require more information， but our funds are limited. We intend to clarify the situation of the support based on the official medical school websites be -cause of the cost effectiveness of this research method. Materials and Methods We define technical words according to Directive 2001/20/EC4 ) • “Investigator": an individual responsible for the conduct of a clinical trial at a clinical institution “Clinical trial":a clinical study that fulfills any of the following conditions: 1.The investigational medicinal products are not authorized. 2. According to the clinical study protoco t，l he in -vestigational medicinal products are not used in ac -cordance with the terms of the marketing authori -zation of the Member State concerned. 3. The assignment of the participant to a particu同 lar therapeutic strategy is decided in advance and does not fall within normal clinical practice of the Member State concerned. 4. The decision to prescribe the investigational medicinal products is made together with the deci -sion to include the participant in the clinical study. 5. Diagnostic or monitoring procedures in addi -tion to normal clinical practice are applied to the partIclpants. “Sponsor": an individual， company， institution， or organization that takes responsibility for the initia -tion and management of the clinical trial “Investigator-initiated clinical trials": clinical trials led by the investigator "Protocol": a document that describes the objec -tives， design， methodology， statistical considera -tions， and organization of a clinical trial We list all medical school websites in
J
apan and find80 medical schools. We check all of the websites including their affiliated hospital websites. First， we intend to locate clinical trial support centers within the medical schools. A researcher checks the we b -sites and searches the following keywords on Goo -gle:“Investigator-initiated clinical trial support" and the name of the medical schooL When there are af -filiated hospitals， we check both school and hospital websites. Generally， a medical school will have its own website and one for its affiliated hospitals.If we are unable to find any support center， we try the keywords “Sponsor同initiatedclinical trial sup -port" and the name of the medical schooL Within the websites， we search using the following key -words:“Clinical trial support，"“consult support，" and “protocol support."W e also search using similar keywords such as“clinical research support" andthe names of the positions responsible for such sup -port.We reject some websites that only show that clinical trials were accepted by an ethics committee or that only provide information for their own workers (because we do not have access to these websites). In the analysis， we distinguish public schools from private schools because public schools seem to provide better support systems. We define nationa p，l refectura and o，l ther public universities and colleges according to some 0旺icialwebsites12)-14). Result There are 51 public medical schools and 29 pri -vate medical schools in
J
apan. All have a旺iliated hospitals and websites. Every medical school has its own center to support clinical trials (Table1).Of the 80 websites， 28 have no mention of investigator -initiated clinical trial support.On 2 of the websites， we are unable to open sections because we are not authorized. All propose sponsor-initiated clinical trial support.Of the 51 public school websites， 36 have description of investigator-initiated clinical trial support compared to 16 of the29 private school websites (Fig.1).There are several support descrip -tions， for example， protocol check and consulting， mail， and format (Table2).We do not check all of the pages， because we lack sufficient time. We only80 medical schools Sorting with some websites σ b - m ， G T A o n u 一 品 供 3 0 白 一 0 4 E L ﹃ 、 J n { 泡 O nLArk ' H p u r 且 a e 口 δ Fig. 1 Flow chart of sorting medical schools Table 2 Protocol support list Document Support method Ethics committee document Document check E-mail Telephone E-mail Telephone Meeting in person Telephone E-mail Others (mail， fax) Lecture A ttending conference E-learning Office communication E-mail for ethics committee Telephone Protocol Format Consu1t Others Communication tool
become aware of support when we insert the key -word in the search system. Discussion All of the medical schools have centers that offer support for clinical trials. We can e旺'ectivelyuse these centers when supporting investigator -initiated clinical trials. We plan to send out question -naires to the centers to determine the ways in which they provide support.Though they support clinical trials， some centers might not offer investigator-initiated clinical trial support.They may provide more support for sponsor-initiated clinical trials than for investigator-initiated clinical trials. We are unable to open some websites; these might include some investigator-initiated clinical trial support.Of the80 checked websites， 26 do not mention investigator-initiated clinical trial suppor，t indicating that they do not0旺er investigator -initiated clinical trial support.Of course， it is possi -ble that they provide some support even though they do not provide relevant information on their websites. We require additional information， be
-cause some investigators may have difficulty find -ing investigator開initiatedclinical trial support infor -mation on the websites. Public schools provide more support information than do private schools. Of the51public schools， 36 (71%) 0旺'erinvestigator -initiated clinical trial support information compared to16of the29 (55%)private schools. This suggests that public schools0旺'ermore support than do pri -vate schools. There are some limitations. First， we only check websites and have no exact support
Drafting protocol Setting protocol 旦E巴竺 Fig.2 Flow chart of protocol setting data. Some websites do not have updated informa -tion. We should contact support center members and ask how they provide support.Second， we can -not know from the websites how much support they provide. We sometimes find some vague sup -port information， like "consulting anytime." In such cases， we do not know the actual support provided， for example， how much consulting is done and by whom. In this website investigation， we check the vague information and get a glimpse at the whole picture of support.We again find it necessary to di -rectly ask those at the centers. Third， a researcher who does the checking might make some mistakes. He double-checks， but there might be some missing support information. Fourth， we select only medical schools， though there are some clinical trials planned in the hospitals or other independent cen -ters like the National Cancer Center and the Na -tional Cerebral and Cardiovascular Center. At times， a small clinic， academic society team， or non -profit organization helpswith investigator司initiated clinical trials. In the future. we will need to investi -gate these support systems. However， we have so many hospitals that might have investigator -initiated clinical trials. For example， it is quite diffi -cult to cover over 2，000 hospitals日 withover 200
beds each. We propose to use a trial registration system like the Medical Schools Hospital Medical
Information Network (UMIN)16)， which can set regis圃
ter formats to demand how they get support and from whom. In the UMIN database， we might not get all trial data， because there are some trials that do not register17 L.)ast， we do not evaluate the ethics committee that helps to improve the protocol (Fig. 2). In order to investigate all support， we need to know more about the ethics committee's work.
Conclusions All centers provide support information about sponsor-initiated clinical trials. We expected that the sponsor-initiated clinical trial support centers of the 80 medical schools may also provide support for investigator-initiated clinical trials. Not all schools mention investigator-initiated clinical trial support. We plan to mail a survey to those cen ters. Acknowledgement We would like to thank the Cooperative Major in Aι vanced Biomedical Sciences， Joint Graduate School of Tokyo Women's Medical University and Waseda Uni -versity teachers for their valuable discussion.
We use funds from the Cooperative Major in Ad -vanced Biomedical Sciences， J oint Graduate School of
Tokyo Women's University and Waseda University. No potential conflicts of interest were disclosed.
References 1)“5 Yearly Clinical Trial Activation Plan 2012". Min -istry of Education， Cu1ture， Sports， Science and Technology， Ministry of Health， Labour and Wel -fare. http://www.mhlw.go.jp/topics/bukyoku/isei/ chiken/ dl/120403_3.pdf (accessed on N ov 30， 2014) 2) Fukui T: Clinical Research in Japan the Status Quo and Problems. Trends In The Sciences 11: 12-17， 2006
3) Study Group How Manage Clinical Trials. Ministry of Health， Labour and Welfare. http://www.mhlw.g o.jp/file/05・shingikai・10801000-Iseikyoku-Soumuka /0000068409.pdf (accessed on April22， 2015) 4) Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approxi -mation of the laws， regulations and administrative practice in the conduct of clinical trials on medici -nal products for human use. Official Journal L 121: 34，2001
5) Goto M， Arakawa Y， Ueda T et al: The Quality Evaluation of Investigator-initiated Clinical Trial Protocols in the University of Tokyo Hospita.lJpn Pharmacol Ther 42: s135-s147， 2014 6) Study Group of J apanese Clinical Trials Problems. The Science Council of Japan. http://www.scj.go.jp /j a/info/kohyo/ pdf/kohyo-22・tl40327.pdf(accessed on Nov 18，2014)
7) McMahon AD， Conway DI， Macdonald T M et al: The unintended consequences of clinical trials regulations. PLoS Med 3: e100013L 2009
8) Ohtsu A: Study Group How Manage Clinical Trials. National Cancer Center Hospital Exploratory On -cology Research & Clinical Trial Center. http://ww w.mhlw.go.jp/file/05・Shingikai-1080 1 000-Iseikyoku -Soumuka/0000049222.pdf (accessed on Nov 30， 2014) 9) Arakawa Y: Recent progress and challenges in investigator-driven clinical development of novel drugs and medical devices at the University of Tokyo Hospita.lYakugaku Zasshi 133: 201 -208， 2013 10) Fujii H: Osaka City University Medical School Hos -pital actions as Core Clinical Research Center. http: / /www.jmacct.med.or.jp/about/h23/files/ act20120 317-tokyol.pdf (accessed on Nov 30， 2014) 11) Clinical Trial Support Center Analysis Abstract. Ministry of Health， Labour and Welfare. http://ww w.mhlw.go.jp/ stf/ shingi/2r9852000002k26f-att/2r9 852000002k53p.pdf (accessed on Nov 30， 2014) 12) National University. Ministry of Education， Culture， Sports， Science and Technology. http://www.mext. go.jp/b_menu/link/daigakul.htm (accessed on Nov 30，2014) 13) Public University. Ministry of Education， Culture， Sports， Science and Technology. http://www.mext. go.jp/b_menu/link/daigaku2.htm (accessed on Nov 30，2014) 14) Japanese Association of Private medical schools. http://wwwi.daikyo.or.jp/top.html (accessed on March 5， 2015)
15) 3rd Committee for Hospital Bed Report and Supply. Ministry of Health， Labour and Welfare. http://ww w.mhlw.go.j p/ stf/ shingi/2r9852000002radO-att/2r9 852000002skuh.pdf (accessed on Nov 30， 2014) 16) UMIN Clinical Trials Registry (UMIN-CTR). http:// www.umin.ac.jp/ctr/index-j.htm (accessed on Nov 30，2014) 17) Kiuchi T， Ishikawa H: Clinical trial registration -current status and future perspective. Jpn J Clin Pharmacol Ther 42: 259-260， 2011
日本における医学部のウェブサイトを用いた研究者主導臨床試験の支援状況調査 東京女子医科大学・早稲田大学共同大学院共同先端生命医科学専攻 ゴ ト ウ マ サ ヤ ア ル ガ アツシ 後 藤 昌 也 ・ 有 賀 淳 〔背景〕日本では臨床研究・治験活性化5ヵ年計画2012で臨床試験を推進している.しかし現在まで日本の 臨床試験には課題が多いとされている.医療施設・機関等の長は，研究者主導臨床試験の支援を行い，かっその 管理を強化させる必要があると言われている.支援が必要であることは言われているが，一方，現在各大学の研 究者主導臨床試験の支援の実態に関して調査は十分に行われていない. 〔方法
