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45 巻 (2014)
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45 巻, 4 号
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特集／臨床試験における欠測データの取扱い：最新の動向
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越前 宏俊2014 年 45 巻 4 号 p. 123
発行日: 2014/07/31
公開日: 2014/08/13
ジャーナル フリーPDF形式でダウンロード (600K) -
折笠 秀樹2014 年 45 巻 4 号 p. 125-129
発行日: 2014/07/31
公開日: 2014/08/13
ジャーナル フリーThe European Medicines Agency issued a guideline on missing data in 2009. In 2012, the U.S. National Research Council published a book on the prevention and treatment of missing data in clinical trials, which has a great impact on medical fields. The most striking fact is that last observation carried forward (LOCF) is not recommended as a primary approach unless the assumption is confirmed. This article overviews some issues on missing data from statistical viewpoints. Prevention of missing data is very important in designing and conducting clinical trials. Once missing data are generated, an appropriate statistical method to handle the missing data is needed after ascertaining the missing mechanism as proposed by Rubin. Most statistical methods assume a mechanism of missing at random (MAR), where a systematic difference between complete and incomplete cases can be explained by a set of observed data. When there are confounding variables influencing missing data, mixed-effects models for repeated measures (MMRM) or other methods can be applied to adjust for confounding factors. Excluding all cases with missing data would usually induce a significant bias. Simple imputation such as LOCF will not be valid unless the underlying assumption is verified. Multiple imputation strategy may be valid under the assumption of MAR. Sensitivity analysis is necessary to confirm the consistency among results obtained by different approaches; for instance comparing intention-to-treat with per protocol set. More accurate reporting on missing data should be strengthened. Pre-specification of handling of missing data is also important in developing a study protocol.抄録全体を表示PDF形式でダウンロード (1363K) -
森田 智視2014 年 45 巻 4 号 p. 131-134
発行日: 2014/07/31
公開日: 2014/08/13
ジャーナル フリーThis article discusses how to handle missing data in the context of clinical trials. First, we review several analytical approaches for the treatment of missing data, such as imputation methods, for handling the complex problem of missing data. Then, we review the definition of missing data and discuss how to handle missing data using real examples.抄録全体を表示PDF形式でダウンロード (765K) -
藤後 修2014 年 45 巻 4 号 p. 135-140
発行日: 2014/07/31
公開日: 2014/08/13
ジャーナル フリーIn clinical trials involving repeated measures, missing data may occur for various reasons. Missing data not only cause loss of information of clinical trials, but are also a potential source of bias and loss of precision of the evaluation results, subsequently may lead to erroneous conclusions. Therefore, efforts to minimize the generation of missing data are necessary when planning to conduct a study. Furthermore, missing data imputation and statistical methods for handling missing data are being examined and discussed in academic societies. From the side of regulatory authorities, the European Medicines Agency (EMA) published the “Guidelines on Missing Data in Confirmatory Clinical Trials” in 2009, which describes the treatment and interpretation of missing data. This article shows our experience of imputation of missing data using modified total sharp score (mTSS), which is an index of joint damage progression, in a clinical trial on patients with rheumatoid arthritis. Some imputation methods and statistical methods are applied to dummy data that are based on the actual clinical trial, and the results are compared and discussed.抄録全体を表示PDF形式でダウンロード (749K) -
飛田 英祐, 原 綾子, 安藤 友紀2014 年 45 巻 4 号 p. 141-146
発行日: 2014/07/31
公開日: 2014/08/13
ジャーナル フリーIn confirmatory clinical trials, missing data may lead to a loss of power and accuracy, and represent a potential source of bias for the estimates of treatment effect (ICH-E9). Recently, the EMA guidelines (2010) and the NAS report in the U.S. (2010) have been published, and missing data has become one of the topics of high interest in biostatistics. In particular, clinical trials in the central neurological disease area (pain and psychiatric disease) have the following characteristics: missing data due to treatment withdrawal or dropout are more frequent than in other disease areas, and the reasons for discontinuation tend to differ between treatment groups. In this paper, we describe the considerations for the handling of missing data, and present actual cases in the central neurological disease area, in which the handling of missing data was discussed in new drug application (NDA) review and consultation at the Pharmaceuticals and Medical Devices Agency (PMDA).抄録全体を表示PDF形式でダウンロード (710K) -
松井 研一2014 年 45 巻 4 号 p. 147-149
発行日: 2014/07/31
公開日: 2014/08/13
ジャーナル フリーMissing data in clinical trials can be handled by appropriate statistical methods, when the data are assumed to be missing at random (MAR). However, whether the missing data are MAR or missing not at random (MNAR) cannot be determined by the nature of the data. Therefore, clinical trials should be designed not only to gather the usual clinical data but to follow incomplete abnormal data from an early stage. Careful attention should be paid to informed consent and the balance between the burden on patients and the collection of precise clinical data.抄録全体を表示PDF形式でダウンロード (722K)
原著
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―クエチアピンおよびプラミペキソールでの検討―松木 俊二, 名取 和一, 小川 幸司, 松井 隆, 松隈 京子, 坂本 慶, 木村 美由紀, 神田 英里, 米納 誠, 伊藤 一弥, 鄭 ...2014 年 45 巻 4 号 p. 151-159
発行日: 2014/07/31
公開日: 2014/08/13
ジャーナル フリーThe aims of the present study were (1) to determine the maximum tolerated doses of quetiapine and pramipexole when given to healthy Japanese male subjects using gradually increasing single doses; (2) to evaluate the feasibility of this exploratory method for further bioequivalence trials; and (3) to conduct bioequivalence trials using doses determined based on prior tolerability trials. For quetiapine, 18 participants received 25 mg in the first stage. In the second stage, participants were divided into three groups of six subjects each and allocated to receive 50 mg, 75 mg or 100 mg depending on the severity of adverse events in the first stage. For pramipexole, 18 participants received 0.125 mg in the first stage, and then received 0.25 mg, 0.375 mg, or 0.5 mg in the second stage in the same manner as quetiapine. In the group receiving 75 mg of quetiapine, three mild adverse events and seven moderate adverse events (including nightmare and syncope) were reported from all six subjects. In the group receiving 0.5 mg of pramipexole, three mild and five moderate adverse events were reported from five subjects. Therefore, we judged that doses equal to or greater than 75 mg of quetiapine and 0.5 mg of pramipexole are not well tolerated by healthy subjects. Based on these results, we conducted two-way crossover bioequivalence clinical trials with brand-name and generic formulations of 25 mg of quetiapine (25 mg tablets or 50% fine granules) and 0.125 mg of pramipexole, in subjects who did not participate in the tolerability studies. By calculating 90% confidence intervals of logarithmic transformed values of Cmax and AUCt, we found that the brand-name and generic formulations were bioequivalent.抄録全体を表示PDF形式でダウンロード (998K)
フォーラム
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植山 茂宏, 岩田 洋子, 森 千鶴, 大塚 好恵, 植山 朋代2014 年 45 巻 4 号 p. 161-168
発行日: 2014/07/31
公開日: 2014/08/13
ジャーナル フリーWe previously reported the psychological issues experienced by parents whose children were undergoing pediatric clinical trials in Japan. The aim of this study was to investigate the psychological burden on parents whose children participated in clinical trials of inhaled corticosteroids with higher risk of adverse effects than other drugs. A questionnaire survey was conducted on 49 parents of 72 children who participated in randomized controlled studies using two types of active trial drugs. Of 49 parents, 23 (47%) responded to the questionnaire at the completion of the trials. Regarding the reason for participating in the trial, 39% of the parents responded that they believed the drugs would have a positive effect, 9% responded that they were convinced by the explanations given during the informed consent procedure, and 9% responded that they had faith in the investigators. At the completion of trials, 87% of the parents were satisfied with participation in the trials, and 87% responded that they would recommend the trials to other parents. However, there were controversial issues and complaints in their responses. Some responses included useful proposals for improving the trials in the future. In conclusion, in the special pediatric trials of inhaled corticosteroids, the parents' psychological belief that the drugs would prove successful and their faith in the principal investigator overcome their anxiety about possible adverse effects of the drugs, which are the motivating force that constitutes the basis for clinical trial implementation. These results show that a robust foundation of clinical care prior to clinical trial involving children ensures more satisfying results for all parties concerned.抄録全体を表示PDF形式でダウンロード (775K)
2012年度 臨床薬理研究振興財団賞学術奨励賞 研究成果報告
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川上 純一 , 内藤 隆文2014 年 45 巻 4 号 p. 169-175
発行日: 2014/07/31
公開日: 2014/08/13
ジャーナル フリーUse of prescription opioids for cancer pain according to the WHO analgesic ladder has been accepted in Japan. A few clinical reports have been published on interindividual variations in pharmacokinetics of and clinical responses to opioid analgesics in cancer patients. This review summarizes our clinical investigations on analgesics in patients with cancer pain. (1) We evaluated the plasma disposition of oxycodone and its demethylates, and dose escalation based on genetic variants of CYP2D6, CYP3A5, ABCB1 and OPRM1 in cancer patients receiving oxycodone. CYP3A5∗3 altered the plasma disposition of noroxycodone and dose escalation in cancer patients receiving oxycodone. CYP3A5∗3 affected the dose escalation of oxycodone by lowering plasma concentrations of noroxycodone. (2) We evaluated the impact of genetic variants of CYP3A5 and ABCB1 on fentanyl pharmacokinetics and clinical responses after switching to a transdermal system. CYP3A5∗3 and ABCB1 C1236T contribute to interindividual differences in clinical response to the fentanyl transdermal system. These genetic variants may predict clinical response to fentanyl in cancer patients converted to the transdermal system. (3) We evaluated the influence of concomitant administration of gabapentin and magnesium oxide or gabapentin and omeprazole on plasma disposition, intestinal absorption, and urinary excretion of gabapentin in healthy subjects. Concomitant magnesium oxide decreased gabapentin exposure through reducting the extent and rate of intestinal absorption. This reduction may be independent of the suppression of gastrointestinal acidification by antacids. Our findings in this review would contribute to optimizing dosage of analgesics including opioids for patients with cancer pain.抄録全体を表示PDF形式でダウンロード (904K)
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