E2082ヒト初回投与試験における被験者死亡を考え...

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E2082ヒト初回投与試験における被験者死亡を考える

フジ虎ノ門整形外科病院内科・精神科

On the death of a study subject in the first in human trial of E2082

Takeo SaioDepartment of Internal Medicine and Psychiatry, Fuji Toranomon Orthopedic Hospital

AbstractBackground：In June 2019, one of the study subjects of a first in human (FIH) trial of an investigational new drug E2082 (ClinicalTrials.gov identifier: NCT03402178) committed suicide probably because of his excruciating psychiatric symptoms. The trial was a repeat-dose study in Japan that aimed to develop an innovative anti-epileptic drug. The symptoms, including apparently auditory and visual hallucination, manifested in the late withdrawal period of the candidate drug. After intensive inspection, the Ministry of Health, Labour and Welfare (MHLW) of Japan issued its investigative report in November 2019.Purpose：To clarify the underlying issues concerning this tragedy from the viewpoint of psychopathology and clinical pharmacology as well as regulatory aspects.Methods：A thorough review of the investigative report issued by the MHLW.Results and Discussion：The differential diagnoses of the case are substance-related: 1) acute confusional state, 2) delirium, 3) withdrawal symptoms, 4) neocortical temporal lobe epilepsy, and 5) postictal psychosis. Although the symptom onset is difficult to determine whether in the dosing or withdrawal period, the psychiatric symptoms grew worse in the withdrawal period, which consequently led to death.Conclusion：As the candidate drug had the potential of psychoactivity, researchers should have developed strategies for the psychiatric symptoms emerging afterward, including re-administration of the candidate drug. The report concluded there was no serious deviation from the Good Clinical Practice (GCP) Ordinance, whereas the descriptions in the report suggested deviations from GCP.

Key wordsadverse events, withdrawal period, psychosis, clinical trial, research regulations

Rinsho Hyoka Clinical Evaluation

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1．はじめに

2．本事案の概要

a．基本的試験デザイン

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b．評価項目

c．選択基準・除外基準

d．被験者の死亡

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Table 1　Inclusion criteria and exclusion criteria

Table 2　Clinical course of the research participant who committed suicide later

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3．本被験者に何が起きたのか：精神病理学的考察

a．精神症候学的検討

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Table 3　Private note written by the deceased participant

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b．精神医学的鑑別診断

c．操作的診断基準による診断

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d．てんかんの可能性 4．臨床薬理学的考察

a．最高用量反復投与での投与中止

Table 4　Differential diagnoses of the case

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b．抗てんかん薬開発早期における脳波測定の必要性

c．治験担当医師の専門性は問題なのか？

d．試験薬再投与の可能性を開くべき

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e．離脱期における精神症状への対応

f．自殺リスク評価尺度

5．GCP適合性に関する考察

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a．被験者の管理

Table 5　Related provisions of the Good Clinical Practice Ordinance cited in the report

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b．被験者に対する情報提供

c．治験実施医療機関の治験実施体制

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d．治験依頼者の治験管理体制

6．本調査の示す今後の対応

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7．まとめ

Table 6　Summary of preventive measures proposed by the regulatory authority

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Table 7　Improvement strategy to prevent similar cases

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E2082ヒト初回投与試験における被験者死亡を考え...

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E2082ヒト初回投与試験における 被験者死亡を考え...

E2082ヒト初回投与試験における被験者死亡を考え...