Research Quality of Clinical Trials Reported for Foods with Function Claims in Japan, 2023-2024: Evaluation Based on a Revised Tool to Assess Risk of Bias in Randomized Trials.

BACKGROUND: The Foods with Function Claim was introduced in Japan in April 2015 to make more products available that are labeled with health functions. A product's functionality of function claims must be explained by the scientific evidence presented in clinical trials (CTs) or systematic reviews, but the quality of recent CTs is unclear. The purpose of this study was to evaluate the risk of bias (RoB) using "a revised tool to assess risk (RoB 2)" published in 2018 for notifications based on all recent CTs published on the Consumer Affairs Agency website. METHODS: A total of 38 submitted papers based on CTs that were published on the Consumer Affairs Agency website during the period from 1 January 2023 to 30 June 2024 were eligible. The RoB 2 tool provides a framework for considering the risk of bias in the findings of any type of randomized trial. This tool with five domains was used to evaluate the quality of research methods. RESULTS: Eligible CTs were assessed as "low risk" (11%, n = 4), "medium risk" (13%, n = 5), and "high risk" (76%, n = 29). A number of highly biased papers were published. Bias occurred in all five domains, especially "bias in selection of the reported result (Domain 5)", which was the most serious ("high risk"; 75%). For elements correlated with RoB, there was no significant difference (p = 0.785) in the RoB 2 score between for-profit and academic research in the author's affiliated organization. There was no significant difference (p = 0.498) in the RoB score between the published year categories of 2000-2019 and 2020-2024, and no significant difference (p = 0.643) in the RoB score between English and Japanese language publications. CONCLUSION: Overall, the quality of the latest CTs submitted after 2023 was very low, occurring in all five domains, and was most serious for "bias in selection of the reported result (Domain 5)".

A Cross-Sectional Study Based on Forty Systematic Reviews of Foods with Function Claims (FFC) in Japan: Quality Assessment Using AMSTAR 2.

BACKGROUND: The Foods with Function Claims (FFC) was introduced in Japan in April 2015 to make more products available that are labeled with health functions. The products' functionality of function claims must be explained by scientific evidence presented in systematic reviews (SRs), but the quality of recent SRs is unclear. This study assessed the quality of SRs in the FFC registered on the Consumer Affairs Agency (CAA) website in Japan. METHODS: We searched the database from 1 April to 31 October 2022. Confidence in the methodological quality of each SR was evaluated by the AMSTAR 2 checklist. RESULTS: Forty SRs were randomly extracted on the basis of the eligibility criteria and recruitment procedures. Overall confidence was rated as "high" (N = 0, 0%), "moderate" (N = 0, 0%), "low" (N = 2, 5%), or "critically low" (N = 38, 95%). The mean AMSTAR 2 score was 51.1% (SD 12.1%; range 19-73%). Among the 40 SRs, the number of critical domain deficiencies was 4 in 7.5% of SRs, 3 in 52.5% of SRs, 2 in 35% of SRs, and 1 in 5% of SRs. Registering the review's protocol and comprehensive search strategies were particularly common deficiencies. Additionally, the risk of bias (RoB) was insufficiently considered. CONCLUSION: Overall, the methodological quality of the SRs based on the FFC, introduced eight years earlier, was very poor. This was especially true in the interpretation and discussion of critical domains, which had many deficiencies in terms of protocol registration, a comprehensive literature search strategy, and accounting for the RoB.

Budget impact analysis of comprehensive genomic profiling for untreated advanced or recurrent solid cancers in Japan.

AIMS: In Japan, the use of comprehensive genomic profiling (CGP) is only available for cancer patients who have no standard of care (SoC), or those who have completed SoC. This may lead to missed treatment opportunities for patients with druggable alterations. In this study, we evaluated the potential impact of CGP testing before SoC on medical costs and clinical outcome in untreated patients with advanced or recurrent biliary tract cancer (BTC), non-squamous non-small cell lung cancer (NSQ-NSCLC), or colorectal cancer (CRC) in Japan between 2022 and 2026. MATERIALS AND METHODS: We constructed a decision-tree model reflecting the healthcare environment of Japan, to estimate the clinical outcome and medical costs impact of CGP testing by comparing two groups (with vs without CGP testing before SoC). The epidemiological parameters, detection rates of druggable alterations, and overall survival were collected from literature and claims databases in Japan. Treatment options selected based on druggable alterations were set in the model based on clinical experts' opinions. RESULTS: In 2026, the number of untreated patients with advanced or recurrent BTC, NSQ-NSCLC, and CRC was estimated to be 8600, 32,103, and 24,896, respectively. Compared with the group without CGP testing before SoC, CGP testing before SoC increased druggable alteration detection and treatment rate with matched therapies in all three cancer types. The medical costs per patient per month were estimated to increase with CGP testing before SoC in the three cancer types by 19,600, 2900, and 2200 JPY (145, 21, and 16 USD), respectively. LIMITATIONS: Only those druggable alterations with matched therapies were considered in the analysis model, while the potential impact of other genomic alterations provided by CGP testing was not considered. CONCLUSIONS: The present study suggested that CGP testing before SoC may improve patient outcomes in various cancer types with a limited and controllable increase in medical costs.

Revisiting the Term "Compassionate Use" and Leadership of the World Health Organization in Resolving Confusion in the Age of COVID-19 and Beyond.

We discuss the term "compassionate use" (CU) as an example of terminology having a huge impact on drug regulation. CU is used in many confusing situations, and its meaning varies significantly. We ethically affirm the necessity of CU. We insist that CU should be properly placed in exceptional status. The regulation of CUs is much more lenient than that of clinical trials because of the difference in the purpose. Whether consciously or unconsciously, abuse results in confusion and is never acceptable. The World Health Organization (WHO) proposed not to use the previous term CU but to replace it with another one. WHO also proposed the term MEURI (monitored emergency use of unregistered and experimental interventions). However, this was extremely incomplete, and WHO used the term CU subsequently. The main purpose of the proposal needs to be thoroughly implemented. In the context of the COVID-19 pandemic and beyond, expectations regarding WHO's role and leadership in global health issues are rising. We hope that WHO will play a major role in promoting research ethics preparedness while discontinuing the use of confusing terms such as CU and will develop alternative terms and their content. We discuss the evaluation of MEURI, the Japanese version of CU, and appropriate and inappropriate terminology related to the therapeutic use of unapproved drugs. We also discuss the expected appearance of CU including its name. It is appropriate to target group/cohort patients and unapproved drugs in the late stage of development. It is also important to solve the problem of incentives for CUs of pharmaceutical companies that are rushing to obtain marketing approval. The UK's Early Access to Medicine Scheme has provided many suggestions. We believe that our opinion can contribute to WHO's efforts to resolve the confusion and promote research ethics preparedness in health emergencies.

[Quality Control and Quality Assurance for the Intermediate Zone between Food and Drug: Rational Use of Such Products and the Need to Modify the Pharmacy Education].

General views on three aspects were discussed. The first aspect is regulatory categories, which can range from "soft to hard", an expression using the English and Japanese translation of the French term, "drogue douce" (soft drug). This categorization starts with "so-called health foods" and extends to Foods with Health Claims [Foods with Nutrient Functional Claims (FNFC); Foods with Functional Claims (FFC); Foods for Specified Health Uses (FOSHU)], OTC drugs, and ethical drugs. "The Basic Policy for New Drug Approval" (1967) made a distinction between OTC and prescription drugs. FOSHU (1991) originally included foods for "patients", such as low allergen rice with preventive "health claims". Foods for Medical Uses (FMU) later became an independent subcategory under Foods for Special Dietary Uses. On the other hand, manufacturers of FFC can make various "health claims" on the basis of randomized controlled trial or systematic review (2015). Products in the intermediate zone between food and drug have an annual market of over 2 trillion yen (US$ 20 billion). The second aspect is the five elements, i.e., quality, safety, efficacy, information, and cost, which are derived from WHO's "The rational use of drugs" (1985). The adoption of Sustainable Development Goals (SDGs) by the UN General Assembly (2015) led to the addition of "ecology" as the sixth element, which is applicable for herbal and animal raw materials. The third aspect is quality control and quality assurance. This initially began with manufactured products and was expanded to the service fields handled by various health workers including pharmacists.

Compliance of Clinical Trial Protocols for Foods with Function Claims (FFC) in Japan: Consistency between Clinical Trial Registrations and Published Reports.

BACKGROUND: A new type of foods with a health claims notification system, the Foods with Function Claims (FFC), was introduced in Japan in April 2015. This cross-sectional study sought to clarify compliance of clinical trial protocols reported as the scientific basis of efficacy in the FFC system. METHODS: All articles based on clinical trials published on the Consumer Affairs Agency website from 1 July 2018 to 30 June 2021 were reviewed. Items assessed included first author characteristics (for-profit or academia), journal name, year published, journal impact factor in 2020, article language, name of clinical trial registration (CTR), and seven compliance items (Title: T, Participant: P, Intervention: I, Comparison: C, Outcome: O, Study design: S, and Institutional Review Board, IRB). Among studies that conducted CTR, consistency with these seven compliance items was evaluated. RESULTS: Out of 136 studies that met all inclusion criteria, 103 (76%) performed CTR, and CTR was either not performed or not specified for 33 (24%). Compliance between the protocol and the text was high (≥96%) for items P and S, but considerably lower for items T, I, C, O, and IRB (52%, 15%, 13%, 69%, and 27%, respectively). Furthermore, 43% of protocols did not include functional ingredients or food names in items T or I. The total score was 3.7 ± 1.1 pts (out of 7). CONCLUSIONS: Some CTs had no protocol registration, and even registered protocols were suboptimal in transparency. In addition to selective reporting, a new problem identified was that the content of the intervention (test food) was intentionally concealed.

Efficacy and safety of tacrolimus in patients with rheumatoid arthritis - A systematic review and meta-analysis.

OBJECTIVES: To evaluate the efficacy and safety of tacrolimus in adult patients with rheumatoid arthritis (RA) by using the GRADE approach. METHODS: We searched PubMed, Japana Centra Revuo Medicina Web (Ichu-shi web), and the Cochrane Database of Systematic Reviews. Articles fulfilling the predefined inclusion criteria were appraised and used for meta-analysis. The primary outcomes were American College of Rheumatology 20 (ACR20) and serum creatinine elevation. Other outcomes included ACR50, ACR70, changes in C-reactive protein, modified Health Assessment Questionnaire Disability Index, gastrointestinal disorders, metabolic and nutritional disorders, and infections and infestations. RESULTS: We identified five randomized controlled studies, four of which compared tacrolimus to placebo and were included in the meta-analysis. The risk ratio of ACR20 achievement was 1.71 (95% confidence interval [CI] 1.20-2.42) for 1-2 mg/day and 2.30 (95% CI 1.79-2.96) for 3 mg/day. The risk ratio of creatinine elevation was 1.95 (95% CI 1.18-3.23) for 1-2 mg/day and 3.81 (95% CI 2.43-5.99) for 3 mg/day. CONCLUSION: Tacrolimus is effective with acceptable safety in the management of RA.

Clinical trial registration, and publication in acupuncture studies: A systematic review.

BACKGROUND: To research 1) how many acupuncture clinical trials are registered with the WHO International Clinical Trial Registry Platform (ICTRP) and what patterns they demonstrate, 2) publication of the articles of acupuncture clinical trials which were registered with ICTRP. METHODS: The search strategy using the ICTRP: Intervention: acupuncture; Recruitment status: All; Date of registration; from 1 Jan 1990 to 31 Dec 2018. We searched the indexed articles in PubMed using trial IDs on 25 Feb 2019. When the paper was published, we indicated the number of weeks from the date of registration with ICTRP to the date of publication in order to define time till the publication. We divided the whole period we analyzed into 6 periods of every 3 years and measured the proportion of publication and the time from the date of registration of each trial till its publication in each period by the Kaplan-Meier method. RESULTS: Forty-three countries/areas conducted at least one acupuncture clinical trial. The total number of registrations was 1758. China, the USA, and the Republic of Korea accounted for 61% of those registrations. The proportion of publication was 178/1758 10% for the fully published papers and 141/1758 8% for the protocol papers. CONCLUSIONS: The substantial increase of registrations by China, the Republic of Korea, Iran, Brazil, Japan was observed which may be attributed to improved awareness of the CONSORT statement. However, the fully published papers rate is low at 10%. The publication of results of acupuncture clinical trials should also be rigorously mandated.

Epidemiological characteristics of rheumatoid arthritis in Japan: Prevalence estimates using a nationwide population-based questionnaire survey.

Objectives: To elucidate the epidemiological characteristics of patients with rheumatoid arthritis (RA) in Japan using data from the Comprehensive Survey of Living Conditions, a nationwide questionnaire survey conducted in 2016.Methods: In total, 222,365 men and 245,251 women aged ≥16 years were included in the study. RA patients were defined as those who reported 'currently receiving treatment for RA at hospitals, clinics, or a facility for Japanese traditional massage, acupuncture, moxibustion, or judo-orthopedics.' The number of RA patients was estimated from the age-specific prevalence and total Japanese population in 2016. Further, the prevalence of individuals experiencing difficulties in activities of daily living due to health problems and those with mental distress as evaluated by K6 Scale was examined.Results: The estimated number and prevalence of RA in Japan with 95% confidence interval was 822 (768-880) thousand and 0.75% (0.70-0.80%). The population peaked in the late 60s, and the prevalence continued increasing until the early 80s, regardless of sex. Compared with non-RA participants, RA patients were more likely to experience difficulties in activities and to be distressed.Conclusion: High prevalence of RA in older age and mental and physical burden among RA patients were confirmed.

Quality of Systematic Reviews of the Foods with Function Claims in Japan: Comparative Before- and After-Evaluation of Verification Reports by the Consumer Affairs Agency.

Background: In Japan, a new type of foods with health claims, called Foods with Function Claims (FFC), was introduced in April 2015 in order to make more products available that are clearly labeled with certain health functions. Regarding substantiating product effectiveness, scientific evidence for the proposed function claims must be explained by systematic reviews (SRs), but the quality of SRs was not clear. The objectives of this review were to assess the quality of SRs based on the FFC registered on the Consumer Affairs Agency (CAA) website in Japan, and to determine whether the CAA's verification report in 2016 was associated with improvement in the quality of SRs. Methods: We evaluated the reporting quality of each SR by the AMSTAR checklist on methodological quality. We searched the database from 1 April to 31 October 2015 as the before-SR and from 1 July 2017 to 31 January 2018 as the after-SR. Results: Among the 104 SRs reviewed, 96 final products were included: 51 (53.1%) were supplements, 42 (43.8%) were processed foods without supplements, and 3 (3.1%) were fresh foods. Of the 104 SRs, 92 (88.5%) were qualitative reviews (i.e., without meta-analysis) and 12 (11.5%) performed a meta-analysis. The average quality score of before-SRs and after-SRs was 6.2 ± 1.8 and 5.0 ± 1.9, respectively, a statistically significant decrease (p < 0.001). Conclusion: Overall, the methodology and reporting quality of after-SRs based on the FFC were poorer than those of before-SRs. In particular, there were very poor descriptions and/or implementations of study selection and data extraction, search strategy, evaluation methods for risk of bias, assessment of publication bias, and formulating conclusions based on methodological rigor and scientific quality of the included studies.