薬理と治療

ここ数年のCOVID‒19 感染拡大の影響により，decentralized clinical trial（DCT）と総称される分散型臨床試験の世界的な潮流が，いま急速に日本にも押し寄せている。本稿では，欧米のDCT の最新動向に加え，ハードとソフト両面の最先端テクノロジーと臨床試験の方法論や実施環境が有機的に融合するDCT platform に焦点を当て，臨床試験の全体最適化について概説する。

医薬品開発，すなわち研究開発から販売承認に至るまで新薬開発コストは約26 億米ドル，6～15 年の期間がかかる1）,2）。また，そのコスト（費用と時間）の2/3 以上は，臨床試験段階に組み込まれているにもかかわらず3），初期臨床試験の85％は失敗に終わり，第3 相試験に達した臨床試験も半分程度の成功率となる4）。さらに，第3 相試験の最大の遅延原因は被験者募集であり，約80％は試験計画時の目標登録症例を満たすことができない5）。そして，この遅延は，製薬企業にとって1 日あたり最大8百万ドルの収入減につながる可能性があり，それゆえ，製薬企業は被験者募集に年間60 億ドル近くのコストを費やしているとされる6）。これらの背景より，近年，治験行為（治験のための診察，検査，投薬など）を治験実施医療機関に集約しない分散型臨床試験（decentralized clinical trial: DCT）が注目されるようになった。

医療に係るリアルワールドデータおよびそれらの解析から生み出されるリアルワールドエビデンス（以下，「医療RWD/RWE」とする）を取り巻く薬事規制の環境は，医薬品，医療機器，再生医療等製品（以下，「医薬品等」とする）の開発，製造販売後のいずれのフェーズにおいても，今まさに，大きな変革を迎えている1）。　まず，医薬品等の臨床開発に関しては，医薬品規制調和国際会議（ICH）におけるE8 ガイドラインの近代化と引き続き行われるE6 ガイドラインの改訂である「GCP Renovation」2）の取り組みがある。E6ガイドライン改訂では，2019 年11 月に発出されたconcept papers およびbusiness plans において，Annex 2 にpragmatic clinical trials やdecentralized clinical trials を組み込んだ臨床試験を対象範囲とする旨が記載されている。この動きは，米国における「21st Century Act」3）において，臨床試験の合理化等による薬事承認迅速化の課題として取り上げられ，適応拡大の承認審査の際に医療RWD/RWE が用いられる事例も出ている。また，日本においても，日本再興戦略（平成27 年6 月30 日閣議決定）において提唱されたクリニカル・イノベーション・ネットワーク（CIN）構想4）のもと，患者レジストリの自然歴研究データを治験対照群として承認審査資料に用いることの検討が進んでいる。　次に，製造販売後に関しては，「医薬品の条件付き早期承認制度について」5）において，医療情報データベース（MID‒NET）事業6）や患者レジストリのような医療RWD/RWE が，承認条件として実施を求める調査等として位置づけられた。また，「医薬品の製造販売後の調査及び試験の実施の基準に関する省令」7）において，MID‒NET 等の医療情報データベースを用いて実施する調査である「製造販売後データベース調査」が新たに規定され，製造販売後の安全性監視活動における医療RWD/RWE の利活用が開始されたところである。　さらに，医薬品医療機器総合機構（PMDA）において，レジストリデータの薬事目的での使用に関する，「承認申請等におけるレジストリの活用に関する基本的考え方」8）および「レジストリデータを承認申請等に利用する場合の信頼性担保のための留意点」9）が検討され，厚生労働省から2021 年3 月23 日に発出されている。　このたび，AMED 柴田班（AMED 医薬品等規制調和・評価研究事業「患者レジストリデータを活用した，臨床開発の効率化に係るレギュラトリーサイエンス研究」班）で議論した，医療RWD/RWE のうち，特に「患者レジストリ」データの薬事目的に関する事項での利活用に関する，レジストリ保有者に対する信頼性確保の具体的な方策について提案した。

医療に係るリアルワールドデータおよびそれらの解析から生み出されるリアルワールドエビデンス（以下，「医療RWD/RWE」とする）を取り巻く薬事規制の環境は，医薬品，医療機器，再生医療等製品（以下，「医薬品等」とする）の開発，製造販売後のいずれのフェーズにおいても，今まさに，大きな変革を迎えている1）。　まず，医薬品等の臨床開発に関しては，医薬品規制調和国際会議（ICH）におけるE8 ガイドラインの近代化と引き続き行われるE6 ガイドラインの改訂である「GCP Renovation」2）の取り組みがある。E6ガイドライン改訂では，2019 年11 月に発出されたconcept papers およびbusiness plans において，Annex 2 にpragmatic clinical trials やdecentralized clinical trials を組み込んだ臨床試験を対象範囲とする旨が記載されている。この動きは，米国における「21st Century Act」3）において，臨床試験の合理化等による薬事承認迅速化の課題として取り上げられ，適応拡大の承認審査の際に医療RWD/RWE が用いられる事例も出ている。また，日本においても，日本再興戦略（平成27 年6 月30 日閣議決定）において提唱されたクリニカル・イノベーション・ネットワーク（CIN）構想4）のもと，患者レジストリの自然歴研究データを治験対照群として承認審査資料に用いることの検討が進んでいる。　次に，製造販売後に関しては，「医薬品の条件付き早期承認制度について」5）において，医療情報データベース（MID‒NET）事業6）や患者レジストリのような医療RWD/RWE が，承認条件として実施を求める調査等として位置づけられた。また，「医薬品の製造販売後の調査及び試験の実施の基準に関する省令」7）において，MID‒NET 等の医療情報データベースを用いて実施する調査である「製造販売後データベース調査」が新たに規定され，製造販売後の安全性監視活動における医療RWD/RWE の利活用が開始されたところである。　さらに，医薬品医療機器総合機構（PMDA）において，レジストリデータの薬事目的での使用に関する，「承認申請等におけるレジストリの活用に関する基本的考え方」8）および「レジストリデータを承認申請等に利用する場合の信頼性担保のための留意点」9）が検討され，厚生労働省から2021 年3 月23 日に発出されている。　本稿では，AMED・柴田班（CIN）で議論した，医療RWD/RWE のうち，特に「患者レジストリ」データの薬事目的に関する事項での利活用に関する信頼性確保の具体的な方策について提案したい。

This is a document for registry holders and investigators of primary studies related to registry establishment, primarily considering rare diseases（rare cancers, rare intractable neurologic diseases, pediatric diseases, etc.）, wherein conducting conventional RCTs is challenging. It describes the points to consider for the operation and management, so as to ensure data reliability while utilizing registry data under the Pharmaceutical Affairs system, especially the utilization of registry data: 1）as an external control of clinical studies for efficacy and/or safety evaluation in applications; 2）to complement or substitute clinical studies for efficacy and/or safety evaluation in applications; and 3）in the evaluation of drugs and medical devices with conditional approval and of regenerative medicine products with conditional and time‒limited approval. 　　Assurance of data quality and reliability of patient registry, and considerations for the protection of personal information require a high level of consciousness and understanding of registry holders and principal investigators, investigators, sub‒investigators, collaborators of primary studies related to registry establishment, health professionals such as physicians at medical institutions generating data; companies that undertake research/ development and manufacturing/marketing of drugs, etc.; and patients and their family members. To promote further utilization of registry data under the Pharmaceutical Affairs system in the future, it is essential to make efforts, in Japan as a whole, and to gain experience and know‒how in many examples. 　　There have been movements such as ICH’s future promotion of GCP renovation and the PMDA’s developmental reorganization of the CIN‒working group and the RWD working group, as well as the utilization of registry data as well as medical RWD/RWE under the Pharmaceutical Affairs system, such as databases based on clinical information collected from electronic medical records, ePRO, and wearable devices. However, their basic principles and points to consider for ensuring reliability, etc., can be conducted based on a discussion of patient registries. 　　The clinical trials conducted in Japan are of high quality due to the uniformity of the evaluation criteria, and the existence of few violations of selection/exclusion criteria, regular visits of subjects, certainty of follow‒up, and data accuracy. These are similar in primary studies related to registry establishment. Creating a mechanism to generate registry data by utilizing such strengths could trigger the practical use of new medical technologies such as drugs in Japan and suitable post‒marketing pharmacovigilance, especially in the field of rare diseases wherein conventional RCTs cannot be conducted.

Background　Face‒to‒face explanation and paper‒based consent acquisition protocol commonly used for obtaining informed consent may increase the risk of infection spread between the participants and the investigators of coronavirus disease（COVID‒19）‒related studies. We examined the use of electronic informed consent（e‒Consent）, obtained through REDCap, an electronic data capture（EDC）system developed by Vanderbilt University, as an alternative. Methods　We utilized the REDCap e‒Consent framework as an alternative to face‒to‒face method for obtaining informed consent in an observational pilot study. We collected requests, inquiries and issues from the pre‒construction to production phase, determined if they are major or minor problems, and analyzed the solutions. We set to judge for the feasibility using EDC like Redcap, if there were no adverse major or minor problems and all participants can complete informed consent with the e‒Consent. Results　Between August and November 2020, a total of 26 participants completed the informed consent from the two centers using REDCap. Since no adverse problems were encountered during e‒consent acquisition, participant enrollment, or data collection, the feasibility was confirmed. Conclusions　Non‒face‒to‒face informed consent can be obtained from study participants using an e‒Consent like REDCap for a single site or a small multicenter study. In cases of a large multisite clinical study, either the site settings should be managed by an organization such as a data center or an alternate method should be used till the usage of e‒Consent is upgraded due to system updates. （Jpn Pharmacol Ther 2022；50 suppl 2：s154‒65）

The Clinical Trials Act was enforced in 2018. At that time, an operating system was newly constructed at Fukushima Medical University Hospital, in order to properly carry clinical studies in compliance with the law. However, investigators in our hospital seemed to get confused because managements based on the study plans were different for each study, and there were many complicated procedures required by the new law. Therefore, flexible support and correspondence were needed. 　We carried out a questionnaire survey for all 19 principal investigators（PIs）who were conducting clinical studies according to the Clinical Trials Act in order to understand the current situation regarding implementation of their studies. This survey included desired duration until the approval of necessary documents by secretariats, burden on required paperwork associated with the law regulations, and acquisition of related funds for the studies that were already being conducted. 　In total, 17 of the 19 PIs completed the survey（89.5％）. The actual lengths for the final approvals of necessary documents were between 2 and 3 weeks, with which many PIs were satisfied. Approximately 80％ of the PIs thought the required paperwork was troublesome. Furthermore, around 70％ of the studies conducted in our hospital according to the Clinical Trials Act were unfunded. This may be one of the factors that reduce the motivation of researchers. In conclusion, the results of our survey revealed the necessity for further reduction of the amount of required paperwork as well as the need for additional funds in order for researchers to actively conduct clinical research according to the Clinical Trials Act. （Jpn Pharmacol Ther 2022；50 suppl 2：s166‒71）

Objectives　This study aimed to propose measures to apply real world data（RWD）for conducting clinical research and to investigate Next Generation Medical Infrastructure Law （NGMIL）enforced 2018 in Japan, by focusing on research with database（DB research）and appropriate framework of funding for universities or clinical research groups to construct medical DB or registry. Methods　We reviewed the current implementation status of DB research in Japan, identified issues, and designed countermeasures for them from the viewpoint of industry‒academia collaboration. We reviewed utilization of medical DB in medical institutions, vendors, and“anonymously processed medical information（MI）handling business operator”defined in NGMIL. In addition, we illustrated configuration of grant for general research（GRG）under the rule of pharmaceutical industry in Japan. Results　The following points were discussed; （1）status of DB research using MI owned by medical institutions and RWD DB constructed after the enforcement of the NGMIL（, 2）status of implementation or examination regarding provision of MI to certified businesses at medical institutions（, 3）notification method, confirmation and recording method to target subjects （patients）（, 4）labor and costs at medical institutions and their acquisition（, 5）status and method of funding from pharmaceutical industries, etc., and（6）impact of relevant laws and guidelines.　　There were few DB research conducted by utilizing large integrated DBs at domestic research institutes. One of the causes was that the most of DB research were designed prospectively, and it was thought that large integrated DBs were not suitable for such purposes.　　Pharmaceutical industries also need to facilitate accumulation of sufficient RWD for analysis. GRG with appropriate funding framework would be a measure.　　On the other hand, medical institutions that provide MI in accordance with the NGMIL are with various burdens. Thus it is also necessary to support them. Conclusions　After the enforcement of the NGMIL, various efforts to promote clinical research utilizing RWD have been made and continued. Lots of issues were found and still remain unresolved. It is necessary for academia and industries to continue to collaborate to address the issues for the future. （Jpn Pharmacol Ther 2022；50 suppl 2：s172‒8）

Background　Since 2015, as an education monitoring group, we have clarified the competencies required for academia monitoring and have implemented education and training plans based on the competencies. However, the Association of Clinical Research Professionals （ACRP）has announced the ACRP Core Competency Framework for overseas Clinical Study Monitoring（ACRP Competency）. The competencies required for academia monitors are changing due to changes in the clinical research implementation environment, such as the enforcement of the Clinical Trials Act. Therefore, we considered reconstructing the competency list in line with the actual situation in Japan. Methods　We prepared a draft competency list required for Japanese academia monitors by comparing the ACRP Competency with the competency list created in 2015. We surveyed by administering a questionnaire（web）to 195 academia monitors to determine the relationship between the degree of competencies and the background of academia monitors. Based on the survey results, the required competencies for each monitor level were examined. Results　The number of respondents in the survey was 59. Academia monitors often serve concurrently with other occupations. It became clear that there was a difference between achievement rate, skills, and attitudes for each background. Based on these results, the competency list for each level was revised. Conclusions　We have revised the level‒based competency list required for academia monitors in line with the actual situation in Japan from a global perspective. Based on this study, we would like to examine the curriculum of monitoring education, verify its validity, and reflect it in the education system. （Jpn Pharmacol Ther 2022；50 suppl 2：s179‒201）