Objective ： Infliximab is a chimeric monoclonal antibody against tumor necrosis factor (TNF) -α that is indicated in the treatment of chronic inflammatory diseases. Infliximab is administered by intravenous infusion and may be associated with infusion related reactions (IRRs). Recent study showed that the use of concomitant antihistamines associated with an increased incidence IRR, using an observational registry database in Canada. The aim of this study was to determine whether the use of concomitant antihistamines associated with an increase in the proportional reporting ratio (PRR) of IRR, using individual case safety reports (ICSRs) with infliximab as one of the suspected drugs, not only from Canada, but also from the United States of America (US), the United Kingdom (UK), and Japan.

Design ： Case-control study

Methods ： We used VigiBase, the WHO's global safety report database, in this study. One-to-one propensity-matching analysis was performed in each country using IBM SPSS version 24 to evaluate outcomes. The primary endpoint was the assessment of concomitant medications associated with IRR in the cases treated with infliximab.

Results ： There were 35,729, 19,095, 4,618, and 1,565 ICSRs in which some adverse events were reported with infliximab as one of the suspected drugs in Canada, the US, the UK, and Japan, respectively, after the exclusion of ICSRs with unknown patient age or unknown patient sex. IRRs were reported in 2,293, 1,427, 303, and 69 ICSRs, respectively. The use of concomitant antihistamines was significantly associated with an increased PRR of IRR in Canada (p<0.001). The uses of concomitant antihistamines were also significantly associated with an increased PRR of IRR in the US (p<0.001), the UK (p<0.001), and Japan (p＝0.007).

Conclusion ： The uses of concomitant antihistamines were associated with an increased PRR of IRR with infliximab in the case-control study using ICSRs from Canada, the US, the UK, and Japan.

Objective: The Charlson and Elixhauser comorbidity indices (CCI and ECI, respectively) are widely used to study comorbid conditions but these indices have not been validated in Japanese datasets. In this study, our objective was to validate and recalibrate CCI and ECI in a Japanese insurance claims database.

Methods: All hospitalizations for patients aged≥18 years discharged between January 2011 and December 2016 were randomly allocated to derivation and validation cohorts. Predictability for hospital death and re-admission was evaluated using C statistics from multivariable logistic regression models including age, sex, and individual CCI/ECI conditions at admission month or the derived score in the derivation cohort. After stepwise variable selection, weighted risk scores for each condition were re-assigned using odds ratios (CCI) or beta coefficients (ECI). The modified models were evaluated in the validation cohort.

Results: The original CCI/ECI had good discriminatory power for hospital death: C statistics (95％ confidence interval) for individual comorbidities and score models were 0.845 (0.835-0.855) and 0.823 (0.813-0.834) for CCI, and 0.839 (0.828-0.850) and 0.801 (0.790-0.812) for ECI, respectively. Modified CCI and ECI had reduced numbers of comorbidities (17 to 10 and 30 to 21, respectively) but maintained comparable discriminatory abilities: C statistics for modified individual comorbidities and score models were 0.843 (0.833-0.854) and 0.838 (0.827-0.848) for CCI, and 0.840 (0.828-0.852) and 0.839 (0.827-0.851) for ECI, respectively.

Conclusions: The original and modified models showed comparable discriminatory abilities and both can be used in future studies using insurance claims databases.

Needless to say, an evidence from the clinical trial is fundamental factor of evidence-based medicine （EBM). However, most of large-scale trials were financially supported by drugindustry companies. As an excursion of large-scale clinical requires huge costs, drug company expects the favorable result for the their test drug. If result fell short of their expectation, sponsored industry try to take some measures, such as the withdrawal of the financial support, or spread the interruption fulfilled with SPIN favoring secondary endpoint in the advertisement.

Recently valsartan related Japanese trials, KYOTO HEART study, which published a too good to be true data, suspected fabricated results and Novartis and ex-employee were charged with false advertising in July 2014. Tokyo District Court ruled that the defendants manipulated clinical evidence in favor of valsartan, although the judge ruled them not guilty on grounds that academic papers were not considered a form of advertising. Several reasons for the misconduct can be raised. Firstly, morality of both investigator and pharmacy were lacking. Secondary, knowledge of investigators about clinical trials and statistics were scarce too much. Thirdly, clinical studies have been started in the circumstance in which insufficient infrastructure development of Japan.

Valsartan scandal led to system changes. The Diet enacted a law aimed at boosting the transparency of clinical research funded by pharmaceutical companies. Research will require to be prescreened by a government accredited committee and ethic committee in the research institution.

A judicial trial in which a pharmaceutical company and a former employee were prosecuted for violation of the Pharmaceutical Affairs Act： the pharmaceutical company and former employees have published papers in academic journals by providing researchers with fake data, such as providing false data disguised as having therapeutic effects on the results of multicenter clinical trials for hypertensive drugs.

Regarding the case, the Tokyo District Court decision on March 16, 2017, and the Tokyo High Court of Appeals decision on November 19, 2020 indicated that both the pharmaceutical company and its former employees were not guilty. The reason is that the Pharmaceutical Affairs Law is a provision that punishes only when false or exaggerated articles are written for advertising purposes, so publication of scientific papers does not apply.

However, there is a question about the interpretation that the provisions of the Pharmaceutical Affairs Law are limited to advertising purposes, and there is room to be identified as advertising purposes from the publication process of the academic dissertation in this case, so I can't agree with the judgment.

The fundamental issues which underlie research misconduct of Diovan case are 1）lack of data-quality control system managed by a competent data manager, 2）absence of trial statistician with sufficient knowledge of methodology (from all the aspects such as scientific, ethical and operating), 3）lack of standard operating procedures (SOPs) to secure blinding of assessors and independence of interim data analysis, which eventually allowed the investigators and statisticians to improperly check and edit crucial data in the midst of the trial. The Biometric Society of Japan, the community of Japanese biostatisticians, issued “The Biometric Society of Japan statement for clinical trials” , established “Statisticians standard of conducts” , and started the Accreditation for Trial Statistician from 2017. Many clinical trials sponsored by universities or research institutes (excluding investigator-initiated TIKEN) are not equipped with SOPs, adequate logistics, and clear responsibility. Moreover, a fair number of so-called “trial statisticians” only provide sample-size calculation and technical aspects of data analysis as statistical consultation. Academia should learn from Diovan case and pursue its role of educating creditable trial statisticians who bear social responsibility and establishing their social status.

Clinical trials play a crucial role in the development of new medical technologies and optimization of current treatments. Because the results directly affect medical practice, the trials must not be harmful both to the current and future patients, which is ensured by their scientific validity and data credibility. Inversely, fake trials deceive and mislead people, representing serious threats to the public welfare.

In 2013, series of misconduct were revealed for Diovan trials, where false results were derived and published, based on made up data. Although futile efforts were devoted to pursue responsibility of relevant researchers and pharmaceutical company, the essential cause was lack of the rule to ensure reliability of clinical studies in academia. Indeed, importance of data credibility, which is a prerequisite of clinical science, was not stipulated in the clinical study ethical guideline, allowing for the spread of studies with poor quality and/or malpractice.

Spurred by the Diovan affairs, national arguments tardily took place regarding reliability of academia trials, leading to the implementation of “Clinical Trials Act”. Although the law will improve reliability of academia trials, several concerns exist, as it ignores external consistency and harmonization with other laws. Most seriously, it lacks the mechanism to translate study achievements to the tangible benefits for people.

Namely, no matter how good results were obtained by studies under the law, they would not lead to the regulatory approval, due to the lack of link with pharmaceutical affairs law. Then, there rises a doubt on the spirit of law, regarding whether it really aims to improve current medicine. Indeed, the driving force of clinical trial is the hope of medical staffs, to palliate the pain of patients and families, if not this time, but next time in the future. This is the cause of clinical trials, where we must return, in order to reward the heart of medicine and clinical trials, for the improvement of academia clinical trial regulation.