Risk Identification Abstractly versus Concretely in Clinical Research in Japan: Randomized and Prospective Research on the Effect of Risk Reduction Activities in a Risk-based Approach

Risk Identification Abstractly versus Concretely in Clinical Research in Japan: Randomized and Prospective Research on the Effect of Risk Reduction Activities in a Risk-based Approach | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk Identification Abstractly versus Concretely in Clinical Research in Japan: Randomized and Prospective Research on the Effect of Risk Reduction Activities in a Risk-based Approach Hidenobu Kondo, Chiu Shih Wei, Yukikazu Hayashi, Naoto Takahashi, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4609382/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Oct, 2024 Read the published version in Therapeutic Innovation & Regulatory Science → Version 1 posted 9 You are reading this latest preprint version Abstract Background The risk-based approach (RBA) was first introduced into studies in 2011–2012. As an RBA, it is important to implement risk reduction activities that are proportionate to risk to effectively reduce avoidable quality problems and ensure that they are well adapted to achieving desired goals. However, there is no consistent methodology for identifying and evaluating risks and planning risk reduction activities. Currently, no research has been performed on identifying and evaluating risks and risk reduction activities. We aimed to evaluate risk reduction activities and their effects by using two risk identification and evaluation methods. Methods Among the risk identification and evaluation methods, the one with the least number of categories or questions for identifying risks [risk assessment form (RAF)] and the one with the highest number [risk assessment tool (RAT)] were selected. Each method was used to identify and evaluate risks and plan risk reduction activities to conduct “research on the blood concentration of ponatinib and treatment outcome in patients with chronic phase chronic myelogenous leukemia (CP-CML).” RAF is a method of identifying risk from abstract questions, and RAT is a method of identifying risks from a list of concrete risks. The sites were randomized into two groups to implement planned risk reduction activities using RAF and RAT and to compare the number of errors and protocol deviations per participant visit between the RAF and RAT groups. Results The number of errors per participant visit was lower in the RAF group than in the RAT group, and the number of protocol deviations per participant was lower in the RAF group than in the RAT group. Conclusions Our study reveals that risk reductions can be successfully implemented by using a method to identify and evaluate risks in a small number of abstract categories that are critical to the quality of clinical research. quality management system risk-based quality management risk-based approach risk identification risk evaluation risk reduction activities Figures Figure 1 Figure 2 Figure 3 Introduction Although it is often successful in achieving a good quality clinical trial, the current practice can be expensive and avoidable quality problems arise in many trials. 1 The commonly cited reason is that the practices in clinical research are not proportionate to risk nor well adapted to achieving desired goals. 1 The guidelines for RBA 1 – 3 have been adopted by the Food and Drug Administration (FDA), European Medicines Association (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) to address these issues. ICH E6(R2) has been specified in RBA. 4 Thus, the FDA, EMA, and PMDA have reflected the RBA in their regulations for each country. 5 – 7 The International Council for Harmonization (ICH) E6–good clinical practice (GCP) (R2) states that “risk reduction activities may be incorporated in protocol design and implementation, monitoring plans, agreements between parties defining roles and responsibilities, systematic safeguards to ensure adherence to standard operating procedures, and training in processes and procedures.” The FDA guideline does not describe risk reduction activities but only describes monitoring activities. 2 However, the EMA Reflection Paper, 1 TransCelerate Position Paper, 8 ECRIN, 9 and Japan Pharmaceutical Manufacturers Association (JPMA) publications 10 – 11 describe training as the details of risk reduction activities. As an RBA, it is important to implement risk reduction activities that are proportionate to risk to effectively reduce avoidable quality problems and ensure that they are well adapted to achieving desired goals. However, there is no consistent methodology for identifying and evaluating risk and planning risk reduction activities. Currently, there are 10 tools of risk identification and evaluation that are open to the public, 9 , 12 – 20 and 8 of them can even be used to develop risk reduction activities. 9 , 12 – 14 , 16 – 18 , 20 The relevance of risk identification and evaluation methods and reducing the scope and frequency of on-site monitoring has been evaluated in the literature. 21 , 22 However, no research has been performed on the relevance of risk identification and evaluation methods and risk reduction activities (e.g., manuals, procedures, instructions, and training), and there is insufficient information about the selection of methods for identifying and evaluating risks and planning risk reduction activities. We aim to evaluate the effects of risk reduction activities by using two risk identification and evaluation methods to help select appropriate risk identification and evaluation methods for planning risk reduction activities. Methods Research Information The main clinical research is on the blood concentration of ponatinib and treatment outcomes in patients with chronic phase chronic myelogenous leukemia (CP-CML) (Clinical Research Registry Number: UMIN000035692). In this study, 17 participants at 13 sites in Japan were randomized. The primary outcome for the main clinical research is the blood concentration of ponatinib for 48 weeks in the MMR achievement and the MMR nonachievement groups. The clinical research data were collected using electronic data capture (EDC), Viedoc. The study chair of the main clinical research was Dr. Naoto Takahashi, Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine. The study coordinator was the Clinical Research Innovation and Education Center, Tohoku University Hospital, and the research sponsor was Otsuka Pharmaceutical Co., Ltd. The Ethics Committee of Tohoku University Graduate School of Medicine in Miyagi, Japan approved our companion study (the approval number is 2022-1-877). It was decided not to obtain additional participant consent because no personal identifiable information was used and no special risks or burdens were associated with participation in our companion study. The method used in our companion study is depicted in Fig. 1 . [insert Fig. 1 .] Selection of Methods to Identify and Evaluate Risks and Plan Risk Reduction Activities In addition to the systematic review of risk-based monitoring tools conducted by Caroline et al., 23 a collection of risk-based monitoring tools ( https://ecrin.org/tools/risk-based-monitoring-toolbox ) in ECRIN was used to collect publicly available methods of risk identification and evaluation. In addition, a search of articles on newly reported methods of risk identification and evaluation since the study conducted by Caroline et al. 23 was conducted in Pubmed. We summarized the information on risk identification and evaluation methods, including the intended use of the results of risk identification and evaluation, risk identification methods, the number of risk categories that are most detailed in each method, and risk evaluation methods in Table 1. Then, we adopted two methods to identify and evaluate risks and plan risk reduction activities in the main clinical research. One of the methods, risk assessment form (RAF), 17 has the least number of risk categories, whereas another, risk assessment tool (RAT), 16 has the highest number of risk categories. RAF was used to identify risks from abstract categories, and RAT was used to select risks from a list of concrete risks. Identifying and Evaluating Risks and Planning Risk Reduction Activities We used two methods—RAF and RAT—to identify and evaluate risk and plan risk reduction activities from October 3, 2018 to December 5, 2018. Risk identification, risk evaluation, and planning of risk reduction activities were first performed using RAF and then with RAT. The activities were performed by 4 data managers (DMs), 2 clinical research associates (CRAs), and 2 statisticians from the Clinical Research Data Center in the Clinical Research Innovation and Education Center, Tohoku University Hospital. An RBA specialist, who has experience in identifying and evaluating risks and planning risk reduction activities in over 10 clinical trials, was the facilitator. The facilitator was required to participate in the study at the time of implementation, but participation by the other members was voluntary, with at least four members participating. One facilitator and one DM have experience in identifying and evaluating risks and planning risk reduction activities in clinical research. When identifying and evaluating risks and planning risk reduction activities using RAF and RAT, we did not differentiate between RAF and RAT participants. The risk reduction activities were planned when communicating the precautions, training processes and procedures, and setting the alert texts to appear on the EDC screen. The alert texts were used to prevent mistakes or protocol deviations but not as a query to correct data entry errors. Deciding on the Sites to Implement Risk Reduction Activities The sites participating in the main clinical research were randomly assigned to the RAF or RAT groups to implement planned risk reduction activities for each group. The randomization was done and stratified according to CRA (n = 3) to ensure approximate balance between RAF and RAT (1:1) and avoid the biases caused by CRA. The RAF and RAT groups were equally likely to appear. The randomized conditions were that the total number of participating sites was 13; the number of CRAs was 3; and the number of sites under the oversight of each CRA was 5, 5, and 3. SAS System Release 9.4 software (SAS Institute Japan Ltd., Tokyo, Japan) and RANUNI functions were used for random number generation. After the randomization, 6 sites were assigned to the RAF group and 7 sites to the RAT group. However, after the assignment, the number of participating sites in the main clinical research decreased to 5 in the RAF group and 7 in the RAT group. Implementation of Risk Reduction Activities The contents and manuscripts of risk reduction activities to communicate the precautions and training were made in Microsoft PowerPoint for the RAF and RAT groups separately. We put the audio of the manuscript readings into slides and created 2 videos for the RAF and RAT groups separately. The risk reduction activities were performed by watching the randomized group video with the investigators and the site staff of every site on the first visit by the CRA. In addition, the slides were distributed to the PI and site staff at the time of the CRA visit. As the risk reduction activities of setting the alert text to appear on the EDC screen, each alert text was described on the EDC screen by the RAF and RAT groups separately. All investigators were trained on the contents of the all risk reduction activities during the investigator meeting prior to the initiation of the main clinical research. The deadline for data entry and the requirement to enter the protocol deviation information into EDC are described in the case report form (CRF) completion guideline. To ensure common risk reductions in the main clinical research, the requirements were provided at all sites. Data collection of errors and protocol deviations The implementers, implementation date, start time, and end time of the risk identification, risk evaluation, and planning of the risk reduction activities were recorded and collected. On-site monitoring, off-site monitoring, and central monitoring were conducted in this study. On-site monitoring was conducted using Partial SDV and SDR, targeting informed consent, eligibility of the study participants, and source documents and data up to 4 weeks visit. If there were any problems in the on-site monitoring up to a 4-week visit, the on-site monitoring was conducted after 24 weeks and after discontinuation or termination. If there were no problems for up to 4 weeks, off-site monitoring was conducted after the 4-week visit. When a serious adverse event (SAE) occurs, on-site or off-site monitoring was conducted. The CRAs queried data that required correction of the electronic case report form (eCRF) and the source data during on-site monitoring. The data queried by the CRAs were used as error data. DMs also created queries after the data check. The data queried by DMs were used as error data only when the data were updated after the query date. The protocol deviation information was obtained by extracting the protocol deviation dataset from the EDC. Analysis of Errors and Protocol Deviations The amount of error data and the number of protocol deviations per subject visit were compared between the RAF and RAT groups. The amount of error data and the number of protocol deviations per person-time taken to implement risk identification and evaluation and planning risk reduction activities were compared between the RAF and RAT groups. The amount of error data was also compared between the data risk categories, which were determined using the impact of data errors, classifying them as high, medium, or low. The high-risk category included critical data related to the protection of human subjects, eligibility criteria, informed consent, and primary endpoints. The medium-risk category included important data not related to the protection of human participants, eligibility criteria, informed consent, and primary endpoints. The low-risk category included all other data not covered by the high- or medium-risk categories. Because all data were classified into high or medium risk categories, none of the data were classified in the low-risk category. To summarize the metrics assessed in this investigation, the following definitions were used: Amount of error data per subject visit in the RAF or RAT group = Number of protocol deviations per subject visit in the RAF or RAT group = Amount of error data per person-time taken to implement risk identification and evaluation and planning risk reduction activities in the RAF or RAT group = Number of protocol deviations per person-time taken to implement risk identification and risk evaluation and plan risk reduction activities in the RAF or RAT group = Results The person-time for risk identification, risk evaluation, and planning risk reduction activities using RAF and RAT were 33.18 and 35.59, respectively (Table 2). The number of risks identified using RAF and RAT, including those withheld at the time of initial risk identification for which no details were determined, was 21 and 41, respectively. The total number of risk reduction activities was 12 in RAF, which are communicating 7 precautions, 4 training in processes and procedures (including the distribution of materials), and 1 setting of alert texts to appear on the EDC screen. The total number of risk reduction activities was 16 in RAT, which are communicating 7 precautions, 5 training in processes and procedures (including the distribution of materials), and 4 setting of alert texts to appear on the EDC screen. The amount of error data per subject visit was lower in the RAF group than in the RAT group, at 1.04 and 1.49, respectively (Fig. 2 ). There were small differences in the data for the high-risk category, with the RAF and RAT groups having 0.68 and 0.75, respectively (Fig. 2 ). There were large differences in the data for the medium-risk category, with the RAF and RAT groups having 0.36 and 0.75, respectively (Fig. 2 ). [insert Fig. 2 .] The number of protocol deviations per subject visit was lower in the RAF group than in the RAT group—0.33 and 0.37, respectively (Fig. 3 ). There were 24 and 42 deviations in RAF and RAT groups, respectively. [insert Fig. 3 .] The amount of error data per person-time taken to implement risk identification and evaluation and planning risk reduction activities was 2.35 in the RAF group and 4.78 in the RAT group (Table 2). The result per subject visit was 0.03 for the RAF group and 0.04 for the RAT group (Table 2). The number of protocol deviations per person-time taken to implement risk identification and evaluation and planning risk reduction activities was 0.75 in the RAF group and 1.18 in the RAT group (Table 2). The result per subject visit was 0.01 for the RAF group and 0.01 for the RAT group (Table 2). Discussion In the GCP Renovation, including ICH E8(R1) and ICH E6(R3), the focus on identifying and evaluating risks and planning risk reduction activities has shifted from the critical data and process to the critical to quality factors. Since the time ICH E6(R2) was issued, various organizations such as pharmaceutical companies, academia, and contract research organizations have been investigating methods for risk identification and evaluation. However, there has been no consensus, and it is difficult to determine the methods that should be used when planning RBA. This study aims to help in the selection of an appropriate method for identifying and evaluating risks and planning risk reduction activities. The amount of error data per subject visit was lower in the RAF group than in the RAT group, and the number of protocol deviations per subject visit was also lower in the RAF group than in the RAT group. The actual number of protocol deviations was also lower in the RAF group than in the RAT group. We identified fewer risks using RAF than RAT. RAF can effectively mitigate risk with fewer categories. These results imply that the RAF method is effective in risk identification and evaluation and risk mitigation planning by identifying specific risks in a small number of abstract categories. While the amount of error data per subject visit in the high-risk category was comparable between the two groups, the number of errors in the medium-risk category in the RAT group was slightly more than twice that of the RAF group. This implies that there is no difference between the two methods in terms of ensuring the reliability of the trial results. The number of error data and protocol deviations per person-time taken to implement risk identification and evaluation and planning risk reduction activities were both lower in the RAF group than in the RAT group. These may be due to differences in the risk identification method. RAF was used to identify risks in 12 abstract categories. RAT was used to select relevant risks from a list of 164 concrete risks. Among the categories in RAF, “Liability” and “Intellectual Proper” in “Organizational Hazards” are not common or similar to any of the categories in RAT. As no risk reduction activity was identified in these categories, the difference in the risk categories might not affect the results. In addition, as RAF has a five-point evaluation for “Impact” and “Likelihood” and RAT has a three-point evaluation for “Severity” and ”Probability,” the two risk evaluation methods are similar, although the number of evaluation points is different. Therefore, the difference in the risk evaluation method might also not affect the results. DMs, CRAs, statisticians from the Clinical Research Data Center in the Clinical Research Innovation and Education Center Tohoku University Hospital, and RBA specialists conducted risk identification and evaluation and planning risk reduction activities in this study. Unlike the members of the research, people who are not familiar with clinical research or people who have no experience in risk identification and evaluation and planning risk reduction activities might be given more time in identifying and evaluating risks and planning risk reduction activities. This might have a significant impact on RAF as it is used to identify risks from 12 abstract categories, and the derivation of risks from abstract questions requires knowledge of clinical research and experience in risk identification, risk evaluation, and planning of risk reduction activities in clinical research. Therefore, risk identification from abstract categories or questions should be employed by those who are familiar with clinical research or who have experience in risk identification, risk evaluation, and risk reduction activities. Otherwise, it may be better to use the method to select relevant risks from a list of concrete risks. The risk reduction activity was implemented, in which the deadline for data entry was described in the CRF completion guideline in both groups for the risk of missing data entry. In the RAF group, an additional risk reduction activity was implemented, in which the precautions and training were conveyed in video. However, the number of missing data entry per subject visit was lower in the RAT group (RAF group: 0.25, RAT group: 0.07). Similarly, the risk reduction activity was implemented, in which the data entry of protocol deviation was described in the CRF completion guideline in both groups for the risk of missing data entry of the deviation. In the RAT group, an additional risk reduction activity was implemented, in which the precautions and training were conveyed in video. The number of missing data entry of protocol deviation per subject visit was lower in the RAF group (RAF group: 0.03, RAT group: 0.07). These results may be due to the difficulty of consciously maintaining the precaution of data entry as the timeliness of data entry is generally trained in clinical research and is not a clinical research-specific precaution for investigators. In addition, although no entry of protocol deviation was considered the clinical research-specific risk, it is general in terms of data entry. Missing data entry may not be effective through risk reduction activities, such as precautions and training. The risk reduction activities were implemented, in which the precaution and training were conveyed in video and the alert text was set to appear on the EDC screen in the RAF group for the missing risk of blood concentration measurement of ponatinib. The number of deviations related to this measurement was lower in the RAF group (RAF group: 0.01, RAT group: 0.04). The risk reduction activity of SAE reporting procedures and the deadline for data entry of SAE were implemented in both groups, and the precautions and training were conveyed in the video. In the RAT group, an additional risk reduction activity was implemented, in which the alert text was set to appear on the EDC screen. The number of deviations related to this measurement was lower in the RAT group (RAF group: 0.03, RAT group: 0.01). All investigators were trained on the contents of the risk reduction activities during the investigator meeting prior to the main clinical study. Therefore, they may be effective in reducing risks in one way communication of intention in the study process, such as by watching movies again as precautions and training and by presenting alert texts on the EDC screen. Our study reveals that protocol deviations are prevented by setting the alert text to appear on the EDC screen, which can be done in addition to training, which is commonly used as a risk-mitigating measure in EMA Reflection Paper, 1 TransCelerate Position paper, 8 ECRIN, 9 and JPMA publications. 10 – 11 In clinical research where CRAs make it difficult to mitigate risks or take preventive actions, setting the alert text to appear on the EDC screen may provide low-cost quality control. In clinical trials conducted by pharmaceutical companies, the CRF design has become more standardized, and such efforts have not been implemented, although they may be effective for critical data. A limitation of our study is that the main clinical research was conducted with a small sample size. Therefore, the results cannot be generalized. In addition, risk identification, risk evaluation, and planning risk reduction activities were carried out by the same members. Preceding planning in RAT by planning in RAF may have affected the results of risk identification, risk evaluation, and planning risk reduction activities. Because 100% SDV and SDR were not conducted in the main clinical research, it may not have collected all the errors and protocol deviations. However, because the scope of monitoring and data review covered all data, it ensured the comparability of RAF and RAT. Our study reveals that it is effective to use RBA to identify risks in a small number of abstract categories. Risk identification, risk evaluation, and planning risk reduction activities are commonly practiced in clinical trials. However, to the best of our knowledge, this is the first study to evaluate the relationship between risk identification and evaluation and risk reduction activities. As critical to quality factors can be considered abstract categories, this evidence is consistent with the policy of risk identification in the GCP Renovation. Conclusion Our study reveals that risk reductions can be successfully implemented by using an appropriate method to identify and evaluate risks in a small number of abstract categories that are critical to the quality of clinical research. This study will help in choosing the appropriate risk identification and evaluation method for planning risk reduction activities. Declarations Conflict of Interest statement The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding statement The main clinical research was sponsored by Otsuka Pharmaceutical Co., Ltd., but the work on our article was not sponsored by any company. Author Contribution HK, CSW, and TY involved in substantial contributions to the conception or design of the work. HK, CSW, TH, NT, and TY performed the acquisition, analysis, or interpretation of the data for the work, and participated in final approval of the version to be published and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. HK, CSW, and TY involved in critical revision for important intellectual content and drafted the work. Acknowledgement We thank Minami Shimada and Munenori Takata for conducting and supporting risk identification, evaluation, and risk control planning. We thank Tomoe Mashiko for conducting the data output. The authors would like to thank Enago (www.enago. jp) for the English language review. This assistance was funded by A2 Healthcare Corporation. We would like to acknowledge the support of all the CRAs and the study team members involved in this clinical research and thank them for their contributions. Finally, I want to express my sincere appreciation to Otsuka Pharmaceutical Co., Ltd. References European Medicines Agency. Science Medicines Health. Reflection Paper on Risk-Based Quality Management in Clinical Trials. London, England: European Medicines Agency; 2013. Publication EMA/269011/2013. US Department of Health and Human Services. Food and Drug Administration. Guidance for Industry: Oversight of Clinical Investigations—A Risk-Based Approach to Monitoring. Washington, DC: US Department of Health and Human Services; 2013. OMB control 0910 – 0733. Ministry. of Health, Labour and Welfare, Evaluation and Licensing Division. Pharmaceutical and food safety bureau. 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Risk analysis and risk adapted on-site monitoring in noncommercial clinical trials. Clin Trails. 2009;6(6):585. OPTIMON. Risk assessment scale en. 2008. Nordic M. Network (NORM). Guideline for a Coordinated GCP-Monitoring of Clinical Trials in the Nordic Countries. 2015. Tudur Smith CT, Williamson P, Jones A, et al. Risk-proportionate clinical trial monitoring: An example approach from a non-commercial trials unit. Trials. 2014;15(1):127. Swiss. Clinical Trial Organisation (SCTO). Guideline for Good Operational Practice version 2.0. 2015. Yee D. University of Minnesota Masonic Cancer Center -Data and Safety Monitoring Plan. 2017. European Clinical Research Infrastructures Network. Integrating activity. Deliverable. D8.08 Guideline on Risk Management for Clinical Research version 1.0. 2015. Brosteanu O, Schwarz G, Houben P, et al. Risk-adapted monitoring is not inferior to extensive on-site monitoring: Results of the adamon cluster-randomised study. Clin Trails. 2017;14(6):584. Journot v. OPTIMON. first results of the French trial on optimisation of monitoring. 2015. https://ssl2.isped.u-bordeaux2.fr/OPTIMON/docs/Communications/2015-Montpellier/OPTIMON%20-%20EpiClin%20Montpellier%202015-05-20%20EN.pdf Accessed September 2018. Hurley C, Shiely F, Power J, et al. Risk-based monitoring (RBM) tools for clinical trials: A systematic review. Contemp Clin Trials. 2016 November;51:15. Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1HidenobuKondo20JUN2024.jpg Table 1. Summary of the risk identification and evaluation methods Table2HidenobuKondo20JUN2024.jpg Table 2.Number of error data and protocol deviations per person-time to implement risk identification, risk evaluation, and planning risk reduction activities in the RAF and RAT groups. * The result per subject visit. Cite Share Download PDF Status: Published Journal Publication published 28 Oct, 2024 Read the published version in Therapeutic Innovation & Regulatory Science → Version 1 posted Editorial decision: Revision requested 29 Jul, 2024 Reviews received at journal 26 Jul, 2024 Reviews received at journal 16 Jul, 2024 Reviewers agreed at journal 05 Jul, 2024 Reviewers agreed at journal 24 Jun, 2024 Reviewers invited by journal 20 Jun, 2024 Editor assigned by journal 20 Jun, 2024 Submission checks completed at journal 20 Jun, 2024 First submitted to journal 20 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Kondo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYBACCQg+IMfA3gNkFjAkEK3FmIHnDJBpYEC8lsQGiRwitUi29x688YHhTnp/Q+7BBz8M/uTxt599+IChxiYalxZpnnPJljMYnuXOOHAu2bDHwKBY4ky6sQHDsbTcBhxa5CRyzKR5/x3ObTjYYybBY2CQuIEhjU2CseEwfi08DIfT5Q/zmP/8A9LC/4z9Bz4t0lAtCQbHeMyYwbZIpLEx4NMi2XPGGOiXw4Ybz/AYS8sYGCfOuPGMWSIBj18kjvcYAkPssLzc/TeGH99UyCX296cxfvhQY4NTCw6QQJryUTAKRsEoGAVoAAAN41gFhfGlDQAAAABJRU5ErkJggg==","orcid":"","institution":"Tohoku University Graduate School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Hidenobu","middleName":"","lastName":"Kondo","suffix":""},{"id":323076433,"identity":"cac60d4e-3ba2-450d-91dd-b2737c1206eb","order_by":1,"name":"Chiu Shih Wei","email":"","orcid":"","institution":"Tohoku University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chiu","middleName":"Shih","lastName":"Wei","suffix":""},{"id":323076434,"identity":"43607b50-05fa-44cf-bd92-c233159b3842","order_by":2,"name":"Yukikazu Hayashi","email":"","orcid":"","institution":"Tohoku University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yukikazu","middleName":"","lastName":"Hayashi","suffix":""},{"id":323076435,"identity":"a3140d3c-0b8f-4b22-8384-f41161951e8b","order_by":3,"name":"Naoto Takahashi","email":"","orcid":"","institution":"Akita University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Naoto","middleName":"","lastName":"Takahashi","suffix":""},{"id":323076436,"identity":"8e747707-904c-477e-a4d5-cd4299b826d2","order_by":4,"name":"Takuhiro Yamaguchi","email":"","orcid":"","institution":"Tohoku University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takuhiro","middleName":"","lastName":"Yamaguchi","suffix":""}],"badges":[],"createdAt":"2024-06-20 05:51:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4609382/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4609382/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s43441-024-00702-w","type":"published","date":"2024-10-28T16:20:10+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60599571,"identity":"24a8c610-5d4c-4267-bb64-80a583b9baea","added_by":"auto","created_at":"2024-07-18 15:58:47","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":94542,"visible":true,"origin":"","legend":"\u003cp\u003eDepiction of the methods used in this study\u003c/p\u003e","description":"","filename":"Figure1HidenobuKondo20JUN2024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4609382/v1/71324e08e8589612175964c5.jpg"},{"id":60599572,"identity":"b549b9ce-6f14-4498-a6cc-656379e0cc1a","added_by":"auto","created_at":"2024-07-18 15:58:47","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":75699,"visible":true,"origin":"","legend":"\u003cp\u003eAmount of error data per subject visit for data risk categories in the RAF and RAT groups\u003c/p\u003e","description":"","filename":"Figure2HidenobuKondo20JUN2024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4609382/v1/9e8ea6f3781ab0097e0c6dc8.jpg"},{"id":60601765,"identity":"d4fcd90c-8cc7-4c61-8a32-db44d9730066","added_by":"auto","created_at":"2024-07-18 16:06:47","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":82624,"visible":true,"origin":"","legend":"\u003cp\u003eNumber of protocol deviations per subject visit in the RAF and RAT groups\u003c/p\u003e","description":"","filename":"Figure3HidenobuKondo20JUN2024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4609382/v1/88d1dee024a2dfd20a13c4eb.jpg"},{"id":68207046,"identity":"06e6f0b7-d587-4031-833a-86a56a07b27d","added_by":"auto","created_at":"2024-11-04 16:34:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":681918,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4609382/v1/ef5b5490-da2d-4497-ae15-7ab82d01e3ca.pdf"},{"id":60599575,"identity":"8448b711-ba9a-4dfc-9c9b-81064ee94bad","added_by":"auto","created_at":"2024-07-18 15:58:47","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":520876,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1. Summary of the risk identification and evaluation methods\u003c/p\u003e","description":"","filename":"Table1HidenobuKondo20JUN2024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4609382/v1/a2e40b04f094ff52c1ad2b83.jpg"},{"id":60602364,"identity":"94355b4f-cc20-40b6-9068-beb617fff8f3","added_by":"auto","created_at":"2024-07-18 16:14:47","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":105209,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2.Number of error data and protocol deviations per person-time to implement risk identification, risk evaluation, and planning risk reduction activities in the RAF and RAT groups. * The result per subject visit.\u003c/p\u003e","description":"","filename":"Table2HidenobuKondo20JUN2024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4609382/v1/7157cdcb74281cee1b3635fe.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk Identification Abstractly versus Concretely in Clinical Research in Japan: Randomized and Prospective Research on the Effect of Risk Reduction Activities in a Risk-based Approach","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAlthough it is often successful in achieving a good quality clinical trial, the current practice can be expensive and avoidable quality problems arise in many trials.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The commonly cited reason is that the practices in clinical research are not proportionate to risk nor well adapted to achieving desired goals.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The guidelines for RBA\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e have been adopted by the Food and Drug Administration (FDA), European Medicines Association (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) to address these issues. ICH E6(R2) has been specified in RBA.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Thus, the FDA, EMA, and PMDA have reflected the RBA in their regulations for each country.\u003csup\u003e\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe International Council for Harmonization (ICH) E6\u0026ndash;good clinical practice (GCP) (R2) states that \u0026ldquo;risk reduction activities may be incorporated in protocol design and implementation, monitoring plans, agreements between parties defining roles and responsibilities, systematic safeguards to ensure adherence to standard operating procedures, and training in processes and procedures.\u0026rdquo; The FDA guideline does not describe risk reduction activities but only describes monitoring activities.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e However, the EMA Reflection Paper,\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e TransCelerate Position Paper,\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e ECRIN,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e and Japan Pharmaceutical Manufacturers Association (JPMA) publications\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e describe training as the details of risk reduction activities. As an RBA, it is important to implement risk reduction activities that are proportionate to risk to effectively reduce avoidable quality problems and ensure that they are well adapted to achieving desired goals. However, there is no consistent methodology for identifying and evaluating risk and planning risk reduction activities.\u003c/p\u003e \u003cp\u003eCurrently, there are 10 tools of risk identification and evaluation that are open to the public,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17 CR18 CR19\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e and 8 of them can even be used to develop risk reduction activities.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe relevance of risk identification and evaluation methods and reducing the scope and frequency of on-site monitoring has been evaluated in the literature.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e However, no research has been performed on the relevance of risk identification and evaluation methods and risk reduction activities (e.g., manuals, procedures, instructions, and training), and there is insufficient information about the selection of methods for identifying and evaluating risks and planning risk reduction activities. We aim to evaluate the effects of risk reduction activities by using two risk identification and evaluation methods to help select appropriate risk identification and evaluation methods for planning risk reduction activities.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eResearch Information\u003c/h2\u003e\n \u003cp\u003eThe main clinical research is on the blood concentration of ponatinib and treatment outcomes in patients with chronic phase chronic myelogenous leukemia (CP-CML) (Clinical Research Registry Number: UMIN000035692). In this study, 17 participants at 13 sites in Japan were randomized. The primary outcome for the main clinical research is the blood concentration of ponatinib for 48 weeks in the MMR achievement and the MMR nonachievement groups. The clinical research data were collected using electronic data capture (EDC), Viedoc. The study chair of the main clinical research was Dr. Naoto Takahashi, Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine. The study coordinator was the Clinical Research Innovation and Education Center, Tohoku University Hospital, and the research sponsor was Otsuka Pharmaceutical Co., Ltd. The Ethics Committee of Tohoku University Graduate School of Medicine in Miyagi, Japan approved our companion study (the approval number is 2022-1-877). It was decided not to obtain additional participant consent because no personal identifiable information was used and no special risks or burdens were associated with participation in our companion study. The method used in our companion study is depicted in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003e[insert Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.]\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eSelection of Methods to Identify and Evaluate Risks and Plan Risk Reduction Activities\u003c/h2\u003e\n \u003cp\u003eIn addition to the systematic review of risk-based monitoring tools conducted by Caroline et al.,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e a collection of risk-based monitoring tools (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ecrin.org/tools/risk-based-monitoring-toolbox\u003c/span\u003e\u003c/span\u003e) in ECRIN was used to collect publicly available methods of risk identification and evaluation. In addition, a search of articles on newly reported methods of risk identification and evaluation since the study conducted by Caroline et al.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e was conducted in Pubmed. We summarized the information on risk identification and evaluation methods, including the intended use of the results of risk identification and evaluation, risk identification methods, the number of risk categories that are most detailed in each method, and risk evaluation methods in Table 1. Then, we adopted two methods to identify and evaluate risks and plan risk reduction activities in the main clinical research. One of the methods, risk assessment form (RAF),\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e has the least number of risk categories, whereas another, risk assessment tool (RAT),\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e has the highest number of risk categories. RAF was used to identify risks from abstract categories, and RAT was used to select risks from a list of concrete risks.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eIdentifying and Evaluating Risks and Planning Risk Reduction Activities\u003c/h2\u003e\n \u003cp\u003eWe used two methods—RAF and RAT—to identify and evaluate risk and plan risk reduction activities from October 3, 2018 to December 5, 2018. Risk identification, risk evaluation, and planning of risk reduction activities were first performed using RAF and then with RAT. The activities were performed by 4 data managers (DMs), 2 clinical research associates (CRAs), and 2 statisticians from the Clinical Research Data Center in the Clinical Research Innovation and Education Center, Tohoku University Hospital. An RBA specialist, who has experience in identifying and evaluating risks and planning risk reduction activities in over 10 clinical trials, was the facilitator. The facilitator was required to participate in the study at the time of implementation, but participation by the other members was voluntary, with at least four members participating. One facilitator and one DM have experience in identifying and evaluating risks and planning risk reduction activities in clinical research. When identifying and evaluating risks and planning risk reduction activities using RAF and RAT, we did not differentiate between RAF and RAT participants. The risk reduction activities were planned when communicating the precautions, training processes and procedures, and setting the alert texts to appear on the EDC screen. The alert texts were used to prevent mistakes or protocol deviations but not as a query to correct data entry errors.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eDeciding on the Sites to Implement Risk Reduction Activities\u003c/h2\u003e\n \u003cp\u003eThe sites participating in the main clinical research were randomly assigned to the RAF or RAT groups to implement planned risk reduction activities for each group. The randomization was done and stratified according to CRA (n = 3) to ensure approximate balance between RAF and RAT (1:1) and avoid the biases caused by CRA. The RAF and RAT groups were equally likely to appear. The randomized conditions were that the total number of participating sites was 13; the number of CRAs was 3; and the number of sites under the oversight of each CRA was 5, 5, and 3. SAS System Release 9.4 software (SAS Institute Japan Ltd., Tokyo, Japan) and RANUNI functions were used for random number generation. After the randomization, 6 sites were assigned to the RAF group and 7 sites to the RAT group. However, after the assignment, the number of participating sites in the main clinical research decreased to 5 in the RAF group and 7 in the RAT group.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eImplementation of Risk Reduction Activities\u003c/h2\u003e\n \u003cp\u003eThe contents and manuscripts of risk reduction activities to communicate the precautions and training were made in Microsoft PowerPoint for the RAF and RAT groups separately. We put the audio of the manuscript readings into slides and created 2 videos for the RAF and RAT groups separately. The risk reduction activities were performed by watching the randomized group video with the investigators and the site staff of every site on the first visit by the CRA. In addition, the slides were distributed to the PI and site staff at the time of the CRA visit. As the risk reduction activities of setting the alert text to appear on the EDC screen, each alert text was described on the EDC screen by the RAF and RAT groups separately. All investigators were trained on the contents of the all risk reduction activities during the investigator meeting prior to the initiation of the main clinical research. The deadline for data entry and the requirement to enter the protocol deviation information into EDC are described in the case report form (CRF) completion guideline. To ensure common risk reductions in the main clinical research, the requirements were provided at all sites.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eData collection of errors and protocol deviations\u003c/h2\u003e\n \u003cp\u003eThe implementers, implementation date, start time, and end time of the risk identification, risk evaluation, and planning of the risk reduction activities were recorded and collected.\u003c/p\u003e\n \u003cp\u003eOn-site monitoring, off-site monitoring, and central monitoring were conducted in this study. On-site monitoring was conducted using Partial SDV and SDR, targeting informed consent, eligibility of the study participants, and source documents and data up to 4 weeks visit. If there were any problems in the on-site monitoring up to a 4-week visit, the on-site monitoring was conducted after 24 weeks and after discontinuation or termination. If there were no problems for up to 4 weeks, off-site monitoring was conducted after the 4-week visit. When a serious adverse event (SAE) occurs, on-site or off-site monitoring was conducted.\u003c/p\u003e\n \u003cp\u003eThe CRAs queried data that required correction of the electronic case report form (eCRF) and the source data during on-site monitoring. The data queried by the CRAs were used as error data. DMs also created queries after the data check. The data queried by DMs were used as error data only when the data were updated after the query date. The protocol deviation information was obtained by extracting the protocol deviation dataset from the EDC.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eAnalysis of Errors and Protocol Deviations\u003c/h2\u003e\n \u003cp\u003eThe amount of error data and the number of protocol deviations per subject visit were compared between the RAF and RAT groups. The amount of error data and the number of protocol deviations per person-time taken to implement risk identification and evaluation and planning risk reduction activities were compared between the RAF and RAT groups. The amount of error data was also compared between the data risk categories, which were determined using the impact of data errors, classifying them as high, medium, or low. The high-risk category included critical data related to the protection of human subjects, eligibility criteria, informed consent, and primary endpoints. The medium-risk category included important data not related to the protection of human participants, eligibility criteria, informed consent, and primary endpoints. The low-risk category included all other data not covered by the high- or medium-risk categories. Because all data were classified into high or medium risk categories, none of the data were classified in the low-risk category. To summarize the metrics assessed in this investigation, the following definitions were used:\u003c/p\u003e\n \u003cp\u003eAmount of error data per subject visit in the RAF or RAT group =\u003c/p\u003e\n \u003cp\u003e\u003cimg 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\u003cp\u003eNumber of protocol deviations per subject visit in the RAF or RAT group =\u003c/p\u003e\n \u003cp\u003e\u003cimg src=\"data:image/png;base64,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\"\u003e\u003c/p\u003e\n \u003cp\u003eAmount of error data per person-time taken to implement risk identification and evaluation and planning risk reduction activities in the RAF or RAT group =\u003c/p\u003e\n \u003cp\u003e\u003cimg src=\"data:image/png;base64,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\"\u003e\u003c/p\u003e\n \u003cp\u003eNumber of protocol deviations per person-time taken to implement risk identification and risk evaluation and plan risk reduction activities in the RAF or RAT group =\u003c/p\u003e\n \u003cp\u003e\u003cimg src=\"data:image/png;base64,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\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe person-time for risk identification, risk evaluation, and planning risk reduction activities using RAF and RAT were 33.18 and 35.59, respectively (Table\u0026nbsp;2). The number of risks identified using RAF and RAT, including those withheld at the time of initial risk identification for which no details were determined, was 21 and 41, respectively. The total number of risk reduction activities was 12 in RAF, which are communicating 7 precautions, 4 training in processes and procedures (including the distribution of materials), and 1 setting of alert texts to appear on the EDC screen. The total number of risk reduction activities was 16 in RAT, which are communicating 7 precautions, 5 training in processes and procedures (including the distribution of materials), and 4 setting of alert texts to appear on the EDC screen.\u003c/p\u003e \u003cp\u003eThe amount of error data per subject visit was lower in the RAF group than in the RAT group, at 1.04 and 1.49, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There were small differences in the data for the high-risk category, with the RAF and RAT groups having 0.68 and 0.75, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There were large differences in the data for the medium-risk category, with the RAF and RAT groups having 0.36 and 0.75, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e[insert Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.]\u003c/p\u003e \u003cp\u003eThe number of protocol deviations per subject visit was lower in the RAF group than in the RAT group\u0026mdash;0.33 and 0.37, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). There were 24 and 42 deviations in RAF and RAT groups, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e[insert Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.]\u003c/p\u003e \u003cp\u003eThe amount of error data per person-time taken to implement risk identification and evaluation and planning risk reduction activities was 2.35 in the RAF group and 4.78 in the RAT group (Table\u0026nbsp;2). The result per subject visit was 0.03 for the RAF group and 0.04 for the RAT group (Table\u0026nbsp;2). The number of protocol deviations per person-time taken to implement risk identification and evaluation and planning risk reduction activities was 0.75 in the RAF group and 1.18 in the RAT group (Table\u0026nbsp;2). The result per subject visit was 0.01 for the RAF group and 0.01 for the RAT group (Table\u0026nbsp;2).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the GCP Renovation, including ICH E8(R1) and ICH E6(R3), the focus on identifying and evaluating risks and planning risk reduction activities has shifted from the critical data and process to the critical to quality factors. Since the time ICH E6(R2) was issued, various organizations such as pharmaceutical companies, academia, and contract research organizations have been investigating methods for risk identification and evaluation. However, there has been no consensus, and it is difficult to determine the methods that should be used when planning RBA. This study aims to help in the selection of an appropriate method for identifying and evaluating risks and planning risk reduction activities.\u003c/p\u003e \u003cp\u003eThe amount of error data per subject visit was lower in the RAF group than in the RAT group, and the number of protocol deviations per subject visit was also lower in the RAF group than in the RAT group. The actual number of protocol deviations was also lower in the RAF group than in the RAT group. We identified fewer risks using RAF than RAT. RAF can effectively mitigate risk with fewer categories. These results imply that the RAF method is effective in risk identification and evaluation and risk mitigation planning by identifying specific risks in a small number of abstract categories. While the amount of error data per subject visit in the high-risk category was comparable between the two groups, the number of errors in the medium-risk category in the RAT group was slightly more than twice that of the RAF group. This implies that there is no difference between the two methods in terms of ensuring the reliability of the trial results.\u003c/p\u003e \u003cp\u003eThe number of error data and protocol deviations per person-time taken to implement risk identification and evaluation and planning risk reduction activities were both lower in the RAF group than in the RAT group. These may be due to differences in the risk identification method. RAF was used to identify risks in 12 abstract categories. RAT was used to select relevant risks from a list of 164 concrete risks. Among the categories in RAF, \u0026ldquo;Liability\u0026rdquo; and \u0026ldquo;Intellectual Proper\u0026rdquo; in \u0026ldquo;Organizational Hazards\u0026rdquo; are not common or similar to any of the categories in RAT. As no risk reduction activity was identified in these categories, the difference in the risk categories might not affect the results. In addition, as RAF has a five-point evaluation for \u0026ldquo;Impact\u0026rdquo; and \u0026ldquo;Likelihood\u0026rdquo; and RAT has a three-point evaluation for \u0026ldquo;Severity\u0026rdquo; and \u0026rdquo;Probability,\u0026rdquo; the two risk evaluation methods are similar, although the number of evaluation points is different. Therefore, the difference in the risk evaluation method might also not affect the results.\u003c/p\u003e \u003cp\u003eDMs, CRAs, statisticians from the Clinical Research Data Center in the Clinical Research Innovation and Education Center Tohoku University Hospital, and RBA specialists conducted risk identification and evaluation and planning risk reduction activities in this study. Unlike the members of the research, people who are not familiar with clinical research or people who have no experience in risk identification and evaluation and planning risk reduction activities might be given more time in identifying and evaluating risks and planning risk reduction activities.\u003c/p\u003e \u003cp\u003eThis might have a significant impact on RAF as it is used to identify risks from 12 abstract categories, and the derivation of risks from abstract questions requires knowledge of clinical research and experience in risk identification, risk evaluation, and planning of risk reduction activities in clinical research. Therefore, risk identification from abstract categories or questions should be employed by those who are familiar with clinical research or who have experience in risk identification, risk evaluation, and risk reduction activities. Otherwise, it may be better to use the method to select relevant risks from a list of concrete risks.\u003c/p\u003e \u003cp\u003e The risk reduction activity was implemented, in which the deadline for data entry was described in the CRF completion guideline in both groups for the risk of missing data entry. In the RAF group, an additional risk reduction activity was implemented, in which the precautions and training were conveyed in video. However, the number of missing data entry per subject visit was lower in the RAT group (RAF group: 0.25, RAT group: 0.07). Similarly, the risk reduction activity was implemented, in which the data entry of protocol deviation was described in the CRF completion guideline in both groups for the risk of missing data entry of the deviation. In the RAT group, an additional risk reduction activity was implemented, in which the precautions and training were conveyed in video. The number of missing data entry of protocol deviation per subject visit was lower in the RAF group (RAF group: 0.03, RAT group: 0.07). These results may be due to the difficulty of consciously maintaining the precaution of data entry as the timeliness of data entry is generally trained in clinical research and is not a clinical research-specific precaution for investigators. In addition, although no entry of protocol deviation was considered the clinical research-specific risk, it is general in terms of data entry. Missing data entry may not be effective through risk reduction activities, such as precautions and training.\u003c/p\u003e \u003cp\u003eThe risk reduction activities were implemented, in which the precaution and training were conveyed in video and the alert text was set to appear on the EDC screen in the RAF group for the missing risk of blood concentration measurement of ponatinib. The number of deviations related to this measurement was lower in the RAF group (RAF group: 0.01, RAT group: 0.04). The risk reduction activity of SAE reporting procedures and the deadline for data entry of SAE were implemented in both groups, and the precautions and training were conveyed in the video. In the RAT group, an additional risk reduction activity was implemented, in which the alert text was set to appear on the EDC screen. The number of deviations related to this measurement was lower in the RAT group (RAF group: 0.03, RAT group: 0.01). All investigators were trained on the contents of the risk reduction activities during the investigator meeting prior to the main clinical study. Therefore, they may be effective in reducing risks in one way communication of intention in the study process, such as by watching movies again as precautions and training and by presenting alert texts on the EDC screen.\u003c/p\u003e \u003cp\u003eOur study reveals that protocol deviations are prevented by setting the alert text to appear on the EDC screen, which can be done in addition to training, which is commonly used as a risk-mitigating measure in EMA Reflection Paper,\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e TransCelerate Position paper,\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e ECRIN,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e and JPMA publications.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e In clinical research where CRAs make it difficult to mitigate risks or take preventive actions, setting the alert text to appear on the EDC screen may provide low-cost quality control. In clinical trials conducted by pharmaceutical companies, the CRF design has become more standardized, and such efforts have not been implemented, although they may be effective for critical data.\u003c/p\u003e \u003cp\u003eA limitation of our study is that the main clinical research was conducted with a small sample size. Therefore, the results cannot be generalized. In addition, risk identification, risk evaluation, and planning risk reduction activities were carried out by the same members. Preceding planning in RAT by planning in RAF may have affected the results of risk identification, risk evaluation, and planning risk reduction activities.\u003c/p\u003e \u003cp\u003eBecause 100% SDV and SDR were not conducted in the main clinical research, it may not have collected all the errors and protocol deviations. However, because the scope of monitoring and data review covered all data, it ensured the comparability of RAF and RAT.\u003c/p\u003e \u003cp\u003eOur study reveals that it is effective to use RBA to identify risks in a small number of abstract categories. Risk identification, risk evaluation, and planning risk reduction activities are commonly practiced in clinical trials. However, to the best of our knowledge, this is the first study to evaluate the relationship between risk identification and evaluation and risk reduction activities. As critical to quality factors can be considered abstract categories, this evidence is consistent with the policy of risk identification in the GCP Renovation.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study reveals that risk reductions can be successfully implemented by using an appropriate method to identify and evaluate risks in a small number of abstract categories that are critical to the quality of clinical research. This study will help in choosing the appropriate risk identification and evaluation method for planning risk reduction activities.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest statement\u003c/h2\u003e \u003cp\u003eThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding statement\u003c/h2\u003e \u003cp\u003eThe main clinical research was sponsored by Otsuka Pharmaceutical Co., Ltd., but the work on our article was not sponsored by any company.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eHK, CSW, and TY involved in substantial contributions to the conception or design of the work. HK, CSW, TH, NT, and TY performed the acquisition, analysis, or interpretation of the data for the work, and participated in final approval of the version to be published and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. HK, CSW, and TY involved in critical revision for important intellectual content and drafted the work.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank Minami Shimada and Munenori Takata for conducting and supporting risk identification, evaluation, and risk control planning. We thank Tomoe Mashiko for conducting the data output. The authors would like to thank Enago (www.enago. jp) for the English language review. This assistance was funded by A2 Healthcare Corporation. We would like to acknowledge the support of all the CRAs and the study team members involved in this clinical research and thank them for their contributions. Finally, I want to express my sincere appreciation to Otsuka Pharmaceutical Co., Ltd.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEuropean Medicines Agency. Science Medicines Health. Reflection Paper on Risk-Based Quality Management in Clinical Trials. London, England: European Medicines Agency; 2013. Publication EMA/269011/2013.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUS Department of Health and Human Services. Food and Drug Administration. Guidance for Industry: Oversight of Clinical Investigations\u0026mdash;A Risk-Based Approach to Monitoring. Washington, DC: US Department of Health and Human Services; 2013. OMB control 0910\u0026thinsp;\u0026ndash;\u0026thinsp;0733.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMinistry. of Health, Labour and Welfare, Evaluation and Licensing Division. Pharmaceutical and food safety bureau. Basic Principles of Risk-Based Monitoring. Tokyo: Ministry of Health. 2013.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInternational Council for Harmonization. Integrated addendum to ICH E6. Clinical Practice. 2016;E6(R2):(R1): Guideline for Good.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEuropean Medicines Agency. Science Medicines Health. Guideline for Good Clinical Practice E6(R2) Step 5. London, England: European Medicines Agency. 2016. Publication EMA/CHMP/\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003eICH/135/1995\u003c/span\u003e\u003cspan address=\"http://ICH/135/1995\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUS Department of Health and Human Services. Food and Drug Administration. OMB Control 0910\u0026thinsp;\u0026ndash;\u0026thinsp;0843. Washington, DC: US Department of Health and Human Services. E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) Guidance for Industry. 2018.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMinistry. of Health, Labour and Welfare, Evaluation and Licensing Division. Pharmaceutical and Food Safety Bureau. Guideline for Good Clinical Practice E6(R2). Step 5. Tokyo: Ministry of Health. 2019.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTransCelerate BioPharma Inc. Risk-Based Monitoring Methodology Position. Paper. 2013.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEuropean Clinical Research Infrastructures Network Transnational Working Groups. Deliverable 13 \u0026amp; 14 Development of a risk assessment tool, assessment of its reliability and definition of a common monitoring strategy and report. 2008.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJapan Pharmaceutical Manufacturers Association. Practical approaches to implementing QMS in clinical trials. 2018. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.jpma.or.jp/information/evaluation/results/allotment/lofurc000000bxq4-att/qms_implementation_201807.pdf\u003c/span\u003e\u003cspan address=\"https://www.jpma.or.jp/information/evaluation/results/allotment/lofurc000000bxq4-att/qms_implementation_201807.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Accessed September 2018.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOsamu K. Hot topics explained in an easy-to-understand manner: What is risk-based monitoring? JPMA NEWS LETTER No.157. 2013. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.jpma.or.jp/about/issue/gratis/newsletter/archive_until2014/pdf/2013_157_03.pdf\u003c/span\u003e\u003cspan address=\"http://www.jpma.or.jp/about/issue/gratis/newsletter/archive_until2014/pdf/2013_157_03.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Accessed September 2018.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTransCelerate BioPharma Inc. Risk-Based Monitoring Methodology Position Paper\u0026mdash;RACT Tool. 2014.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMRC/DH/MHRA Joint Project. Risk-Adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products. 2011.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrosteanu O, Houben P, Ihrig K, et al. Risk analysis and risk adapted on-site monitoring in noncommercial clinical trials. Clin Trails. 2009;6(6):585.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOPTIMON. Risk assessment scale en. 2008.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNordic M. Network (NORM). Guideline for a Coordinated GCP-Monitoring of Clinical Trials in the Nordic Countries. 2015.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTudur Smith CT, Williamson P, Jones A, et al. Risk-proportionate clinical trial monitoring: An example approach from a non-commercial trials unit. Trials. 2014;15(1):127.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSwiss. Clinical Trial Organisation (SCTO). Guideline for Good Operational Practice version 2.0. 2015.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYee D. University of Minnesota Masonic Cancer Center -Data and Safety Monitoring Plan. 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEuropean Clinical Research Infrastructures Network. Integrating activity. Deliverable. D8.08 Guideline on Risk Management for Clinical Research version 1.0. 2015.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrosteanu O, Schwarz G, Houben P, et al. Risk-adapted monitoring is not inferior to extensive on-site monitoring: Results of the adamon cluster-randomised study. Clin Trails. 2017;14(6):584.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJournot v. OPTIMON. first results of the French trial on optimisation of monitoring. 2015. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ssl2.isped.u-bordeaux2.fr/OPTIMON/docs/Communications/2015-Montpellier/OPTIMON%20-%20EpiClin%20Montpellier%202015-05-20%20EN.pdf\u003c/span\u003e\u003cspan address=\"https://ssl2.isped.u-bordeaux2.fr/OPTIMON/docs/Communications/2015-Montpellier/OPTIMON%20-%20EpiClin%20Montpellier%202015-05-20%20EN.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Accessed September 2018.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHurley C, Shiely F, Power J, et al. Risk-based monitoring (RBM) tools for clinical trials: A systematic review. Contemp Clin Trials. 2016 November;51:15.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"therapeutic-innovation-and-regulatory-science","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tirs","sideBox":"Learn more about [Therapeutic Innovation \u0026 Regulatory Science](https://link.springer.com/journal/43441)","snPcode":"43441","submissionUrl":"https://www.editorialmanager.com/tirs/default.aspx","title":"Therapeutic Innovation \u0026 Regulatory Science","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"quality management system, risk-based quality management, risk-based approach, risk identification, risk evaluation, risk reduction activities","lastPublishedDoi":"10.21203/rs.3.rs-4609382/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4609382/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe risk-based approach (RBA) was first introduced into studies in 2011\u0026ndash;2012. As an RBA, it is important to implement risk reduction activities that are proportionate to risk to effectively reduce avoidable quality problems and ensure that they are well adapted to achieving desired goals. However, there is no consistent methodology for identifying and evaluating risks and planning risk reduction activities. Currently, no research has been performed on identifying and evaluating risks and risk reduction activities. We aimed to evaluate risk reduction activities and their effects by using two risk identification and evaluation methods.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAmong the risk identification and evaluation methods, the one with the least number of categories or questions for identifying risks [risk assessment form (RAF)] and the one with the highest number [risk assessment tool (RAT)] were selected. Each method was used to identify and evaluate risks and plan risk reduction activities to conduct \u0026ldquo;research on the blood concentration of ponatinib and treatment outcome in patients with chronic phase chronic myelogenous leukemia (CP-CML).\u0026rdquo; RAF is a method of identifying risk from abstract questions, and RAT is a method of identifying risks from a list of concrete risks. The sites were randomized into two groups to implement planned risk reduction activities using RAF and RAT and to compare the number of errors and protocol deviations per participant visit between the RAF and RAT groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe number of errors per participant visit was lower in the RAF group than in the RAT group, and the number of protocol deviations per participant was lower in the RAF group than in the RAT group.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur study reveals that risk reductions can be successfully implemented by using a method to identify and evaluate risks in a small number of abstract categories that are critical to the quality of clinical research.\u003c/p\u003e","manuscriptTitle":"Risk Identification Abstractly versus Concretely in Clinical Research in Japan: Randomized and Prospective Research on the Effect of Risk Reduction Activities in a Risk-based Approach","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 15:58:42","doi":"10.21203/rs.3.rs-4609382/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-29T12:44:09+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-26T18:58:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-16T14:21:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"213251502024786626855887510150690512615","date":"2024-07-05T09:21:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"113881064636899358340478603233903945526","date":"2024-06-24T18:23:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-20T18:27:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-20T17:48:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-20T12:40:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Therapeutic Innovation \u0026 Regulatory Science","date":"2024-06-20T05:48:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"therapeutic-innovation-and-regulatory-science","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tirs","sideBox":"Learn more about [Therapeutic Innovation \u0026 Regulatory Science](https://link.springer.com/journal/43441)","snPcode":"43441","submissionUrl":"https://www.editorialmanager.com/tirs/default.aspx","title":"Therapeutic Innovation \u0026 Regulatory Science","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"aa854e74-9c9f-4fe2-a88f-462dbc5a78e2","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-04T16:25:55+00:00","versionOfRecord":{"articleIdentity":"rs-4609382","link":"https://doi.org/10.1007/s43441-024-00702-w","journal":{"identity":"therapeutic-innovation-and-regulatory-science","isVorOnly":false,"title":"Therapeutic Innovation \u0026 Regulatory Science"},"publishedOn":"2024-10-28 16:20:10","publishedOnDateReadable":"October 28th, 2024"},"versionCreatedAt":"2024-07-18 15:58:42","video":"","vorDoi":"10.1007/s43441-024-00702-w","vorDoiUrl":"https://doi.org/10.1007/s43441-024-00702-w","workflowStages":[]},"version":"v1","identity":"rs-4609382","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4609382","identity":"rs-4609382","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}