임상시험 피험자에게 발생하는 이상반응 관리 절차의 문제점과 개선방안

이미성 이화여자대학교 생명의료법연구소 2010 생명윤리정책연구 Vol.4 No.2

Institutional Review Board (IRB) is a committee to protect clinical research subjects’ human rights and health and to guarantee the ethicality and scientificity of research. However, the adverse event report system of domestic IRBs is not playing its role adequately as a subject protection against adverse events in clinical trials. According to the SOPs of the IRBs of five hospitals surveyed, convened IRB review is judged relying on reports submitted by the investigator, and adverse events not included in the convened IRB review are reviewed in the Expedite Review or not reviewed. This report system can be a problem in three aspects. First, the investigator may submit a wrong report because of financial or non-financial conflict of interest. Second, the investigator may misdiagnose adverse events occurring in the subjects. Third, there is no system for detecting errors even if the investigator has made an incorrect report on adverse events. In order to solve these problems, this study made a number of suggestions. First, in order to manage investigators’ conflict of interest, the IRB needs to establish SOPs related to conflict of interest and KGCP should also introduce provisions on conflict of interest. Second, in consideration of the investigator’s misdiagnosis, it is proposed to use the peer review system. It is introducing ‘second opinions on adverse events’ from medical specialists in the same major. Lastly, in order to detect errors in the investigator’s report, it is suggested to utilize a committee specializing in the review of adverse events (adverse event committee). The Special Committee on Adverse Events is a subcommittee mainly on adverse events. Such a committee may provide a more professional and intensive review for adverse events. Subject protection in the true sense cannot be attained by simple documentary works or by following a procedure. Thus, it is now necessary to see adverse event reviews are made meaningfully to individual subjects.

국내 임상시험 이상반응의 IRB 보고 및 관리현황

이세현,김영인,임현우,이귀향,최병인 대한임상약리학회 2011 Translational and Clinical Pharmacology Vol.19 No.2

Background: This research is to identify the difficulties occuring in the course of managing the adverse events and the adverse event related standard operating procedure in the regulation of each institutional review board. Methods: In order to identify the issues of the management of adverse events of each institution, this research surveyed the IRB administrators in fifty two university hospitals nation-wide. This survey is conducted among one chairman and one IRB member from the IRB members per each IRB who have experience in reviewing adverse events. The survey also includes investigators and sponsors who engage in reporting adverse events. Results: The result of this survey demonstrates that the objects and the terms of adverse event reports provided by the Standard Operating Procedure and the KGCP of each institution are not very different from each other. However, according to the survey, any cases reported to the IRBs, although they are not specified as the object of reports in the institution, have been reviewed by the IRB members. To sum up the results of the survey, the major issues include ambiguous regulations on adverse event reports and reviews, the use of different report formats for each institution, and the difficulty with evaluating the causal relationship with Investigational Product. Conclusion: It is necessary to develop concrete and specified guidelines on the objects and the terms of reports, the standard for the causal relationship and the adequate measures for adverse events after review and to standardize the format of adverse event reporting.

A randomized, observer-blinded, equivalence trial comparing two variations of Euvichol®, a bivalent killed whole-cell oral cholera vaccine, in healthy adults and children in the Philippines ^☆

Russo, Paola,Ligsay, Antonio D.,Olveda, Remigio,Choi, Seuk Keun,Kim, Deok Ryun,Park, Ju Yeon,Park, Ju Yeong,Syed, Khalid Ali,Dey, Ayan,Kim, Yang Hee,Lee, Sung Hee,Kim, Jayoung,Chon, Yun,Digilio, Laura Elsevier Science 2018 Vaccine Vol.36 No.29

<▼1><P><B>Highlights</B></P><P>•<P>Bridging study demonstrating the equivalence of two variations of Euvichol®.</P>•<P>The 600L thimerosal-free Euvichol® is safe and immunogenic in adults and children.</P>•<P>The scale-up of Euvichol® allows expanding global access to oral cholera vaccine.</P></P></▼1><▼2><P><B>Background</B></P><P>To contribute to the global demand for oral cholera vaccine (OCV), the production of Euvichol® was scaled up with elimination of thimerosal. To demonstrate the equivalence of the variations, a study was carried out in the Philippines.</P><P><B>Methods</B></P><P>Healthy male and female adults and children in Manila were randomized to receive two doses of Euvichol® two weeks apart from either the 100L (Comparator) or the 600L (Test) variation. Primary and secondary immunogenicity endpoints were respectively geometric mean titer (GMT) of vibriocidal antibodies (two weeks post second dose) and seroconversion rate (two weeks after each dose) against O1 Inaba, Ogawa, and O139 serogroups. The GMT of vibriocidal antibodies against O1 Inaba, Ogawa, and O139 two weeks post first dose was also measured. To show the equivalence of two variations of Euvichol®, the ratio of GMT and the difference of seroconversion rate between Test and Comparator vaccines were tested with equivalence margin of [0.5, 2.0] for GMT ratio and of 15% for seroconversion rate, respectively. Safety assessment included solicited reactogenicity within 6 days after each dose and unsolicited and serious adverse events.</P><P><B>Results</B></P><P>A total of 442 participants were enrolled. For the overall population, equivalence between Test and Comparator was demonstrated for vibriocidal antibody response against O1 Inaba and Ogawa serotypes and O139 serogroup in both modified intention-to-treat (mITT) and per protocol analysis, since the 95% confidence intervals (CI) of GMT to any serotypes were within the lower and upper boundary [0.5, 2.0]. Seroconversion rates after two doses also showed equivalence for O1 Inaba, Ogawa, and O139. The vaccine was safe and well tolerated, similarly between the two groups.</P><P><B>Conclusion</B></P><P>The study results support the equivalence of the 600L Euvichol® to the 100L formulation in healthy children and adults. The 600L Euvichol® is safe and immunogenic in adults and children.</P><P>ClinicalTrials.gov registration number: NCT02502331.</P></▼2>

임상시험에서 이상반응 분류 시 MedDRA를 기반으로 한 자동코딩시스템 개발

전은정,임현우,최인영,송길룡,이영작,이경신 대한임상약리학회 2009 Translational and Clinical Pharmacology Vol.17 No.2

Introduction: Currently, the adverse events are being inspected, aiming to prove the safety from phase 1 up to phase 4 of clinical study to Post Marketing Surveillance (PMS). Along with the movement of the changing international society, an auto coding system that is developed based on the existing MedDRA was devised to provide medically consistent and accurate as well as commonly applicable terminologies in the field of medicine while aiming to share the clinical safety of the medical supplies oriented by the ICH countries. Material and Methods: The auto coding system developed in this study basically connected the 67,159 LLT terminologies from MedDRA 12.0 and 5,583 terminologies from WHO-ART 2006, while improving the coding efficiency by utilizing the existing coding data. As for the comparison between the Copy & Paste Method (Hereinafter called as ‘CPM’) and AE Mapper (Hereinafter called as ‘AEM’), which was an auto coding system, the assessment was made in terms of efficiency, accuracy, and consistency. In addition, the difference depending on the level of medical background among the coders’ skill was measured when comparing CPM and AEM. Result: In case of comparing CPM and AEM, the time consumed for CPM was 5.3 times greater in experiment 1, 3.9 times greater in experiment 2, and 4.5 times greater in both experiments 1 and 2 compared to the results derived from AEM. When comparing the accuracy, the file of the experiment 1 did not display a significant difference resulting CPM 86.7% and AEM 94.9% of the total average; however, the file of experiment 2 showed a significant difference as CPM was 62.0% and AEM was 92.4% in terms of the total average. When comparing the Consistency, the file of the experiment 1 did not display a significant difference resulting CPM 89.0% and AEM 99.3% of the total average; however, the file of experiment 2 showed a significant difference as CPM was 79.6% and AEM was 98.9% in terms of the total average. Conclusion: Based on the result derived by comparing CPM that copied and pasted AE and AEM (AE Mapper) that was an auto coding system for coding AE, it was known that the use of the auto coding system was superior in terms of efficiency, accuracy, and consistency. Furthermore, when using the auto coding system, there was no significant difference depending on the users’ medical background and past experience in terms of accuracy and agreement compared to the CPM. Therefore, it is suggested to seek a method to improve the mapping of the auto coding system and conduct a further study that applies such system. Introduction: Currently, the adverse events are being inspected, aiming to prove the safety from phase 1 up to phase 4 of clinical study to Post Marketing Surveillance (PMS). Along with the movement of the changing international society, an auto coding system that is developed based on the existing MedDRA was devised to provide medically consistent and accurate as well as commonly applicable terminologies in the field of medicine while aiming to share the clinical safety of the medical supplies oriented by the ICH countries. Material and Methods: The auto coding system developed in this study basically connected the 67,159 LLT terminologies from MedDRA 12.0 and 5,583 terminologies from WHO-ART 2006, while improving the coding efficiency by utilizing the existing coding data. As for the comparison between the Copy & Paste Method (Hereinafter called as ‘CPM’) and AE Mapper (Hereinafter called as ‘AEM’), which was an auto coding system, the assessment was made in terms of efficiency, accuracy, and consistency. In addition, the difference depending on the level of medical background among the coders’ skill was measured when comparing CPM and AEM. Result: In case of comparing CPM and AEM, the time consumed for CPM was 5.3 times greater in experiment 1, 3.9 times greater in experiment 2, and 4.5 times greater in both experiments 1 and 2 compared to the results derived from AEM. When comparing the accuracy, the file of the experiment 1 did not display a significant difference resulting CPM 86.7% and AEM 94.9% of the total average; however, the file of experiment 2 showed a significant difference as CPM was 62.0% and AEM was 92.4% in terms of the total average. When comparing the Consistency, the file of the experiment 1 did not display a significant difference resulting CPM 89.0% and AEM 99.3% of the total average; however, the file of experiment 2 showed a significant difference as CPM was 79.6% and AEM was 98.9% in terms of the total average. Conclusion: Based on the result derived by comparing CPM that copied and pasted AE and AEM (AE Mapper) that was an auto coding system for coding AE, it was known that the use of the auto coding system was superior in terms of efficiency, accuracy, and consistency. Furthermore, when using the auto coding system, there was no significant difference depending on the users’ medical background and past experience in terms of accuracy and agreement compared to the CPM. Therefore, it is suggested to seek a method to improve the mapping of the auto coding system and conduct a further study that applies such system.

Repeated Administration of Newly Synthesized Aceclofenac Sustained Release Form Causes Agranulocytosis: Case Report of an Unforeseen Adverse Event during the Phase 1 Trial

Hui Jin,Renhua Zheng,김보형,임성빈 대한임상약리학회 2014 Translational and Clinical Pharmacology Vol.22 No.1

Aceclofenac is a non-steroidal anti-inflammatory drug (NSAIDs) for inflammatory diseases. In this report, we report a serious adverse event (AE) occurred during the phase I clinical trial for a new sustained-release (SR) formulation of aceclofenac. There was a serious adverse event (AE), agranulocytosis, induced by aceclofenac SR form. An open-labeled, repeated-doses, randomized, crossover study was conducted at Kyung Hee University Hospital and 26 Korean healthy male volunteers were enrolled. All subjects received both aceclofenac SR 200 mg once daily and aceclofenac IR 100 mg twice daily for 4 days with 11 days washout period. After 11 days washout period, one subject showed a serious decrease in the segment neutrophil (267/mm3) on a laboratory test prior to the reference drug administration in period 2. We first report a case of agranulocytosis, during a phase I clinical trial.