Validation of algorithms in studies based on routinely collected health data: general principles.

Clinicians, researchers, regulators, and other decision-makers increasingly rely on evidence from real-world data (RWD), including data routinely accumulating in health and administrative databases. RWD studies often rely on algorithms to operationalize variable definitions. An algorithm is a combination of codes or concepts used to identify persons with a specific health condition or characteristic. Establishing the validity of algorithms is a prerequisite for generating valid study findings that can ultimately inform evidence-based health care. This paper aims to systematize terminology, methods, and practical considerations relevant to the conduct of validation studies of RWD-based algorithms. We discuss measures of algorithm accuracy; gold/reference standard; study size; prioritizing accuracy measures; algorithm portability; and implication for interpretation. Information bias is common in epidemiologic studies, underscoring the importance of transparency in decisions regarding choice and prioritizing measures of algorithm validity. The validity of an algorithm should be judged in the context of a data source, and one size does not fit all. Prioritizing validity measures within a given data source depends on the role of a given variable in the analysis (eligibility criterion, exposure, outcome or covariate). Validation work should be part of routine maintenance of RWD sources.

Comparison of the incidence of bleeding between baloxavir marboxil and other anti-influenza drugs among outpatients with influenza virus infection: A retrospective cohort study using an employment-based health insurance claims database in Japan.

PURPOSE: Alerts for bleeding events are included in the Japanese package inserts of some anti-influenza drugs, including baloxavir marboxil and oseltamivir. However, there are few reports on the incidence of bleeding events during treatment with anti-influenza drugs. This large-scale quantitative assessment compared the incidence of bleeding events in influenza patients treated with baloxavir and other anti-influenza drugs and in untreated patients. METHODS: This retrospective cohort study used a large-scale Japanese employment-based health insurance claims database provided by JMDC Inc. and included outpatients diagnosed with influenza between October 1, 2018 and April 11, 2019. Bleeding events were identified by International Classification of Diseases 10th revision codes. Incidences were compared between patients treated with baloxavir or neuraminidase inhibitors and untreated patients. Odds ratios were calculated after exact matching to adjust for potential confounders. RESULTS: Among 529 201 influenza episodes, 30 964 were untreated and 498 237 were treated with anti-influenza drugs: baloxavir, 207 630; oseltamivir, 143 722; zanamivir, 28 208; peramivir, 5304; laninamivir, 113 373. Crude incidence proportions for total bleeding up to 20 days after influenza diagnosis were similar among treated groups, with a slightly higher value for peramivir (0.21% vs. 0.19% for baloxavir, oseltamivir, zanamivir, and laninamivir), and 0.30% in untreated patients. After exact matching, the incidence of bleeding for baloxavir was similar to that for other anti-influenza treatments (odds ratios for baloxavir were 0.90-0.99 compared to other therapies). CONCLUSIONS: Based on real-world observation using a large-scale claims database, a similar incidence of bleeding events was observed in recipients of the different anti-influenza drugs.

Behavioral changes and hygiene practices of older adults in Japan during the first wave of COVID-19 emergency.

BACKGROUND: On April 7, 2020, Japan declared a state of emergency due to the first wave of coronavirus disease 2019 (COVID-19) with the associated social distancing likely to have had a great impact on older adults' lifestyle and health. This study aimed to explore the behavioral changes and personal hygiene practices in relation with background psychosocial and health characteristics of older adults during the COVID-19 emergency. METHODS: A cross-sectional telephonic survey was conducted with the participants of the Kawasaki Aging and Wellbeing Project (KAWP), an on-going longitudinal cohort study of older adults aged 85 or older. The interviews were conducted using a structured questionnaire consisting of 11 closed questions regarding behavioral changes and personal hygiene practices during the state of emergency. Sociodemographic and health data were obtained from the KAWP baseline survey conducted 2.2 years before the telephonic survey. RESULTS: Overall, 487 participants from the KAWP responded to the telephonic survey (response rate: 89.2%). 94.5% of the respondents reported no changes in basic lifestyle habits, such as eating, sleeping, smoking, and drinking, whereas 28.1% reported a decrease in physical activity, and 54.6% reported going out less frequently. One-third of the respondents reported a decrease in the number of people to converse with, as well as the amount of time to converse. For personal hygiene practices, 93.8% reported wearing a mask when they went out, and 50.3% reported an increased frequency of handwashing. Multiple logistic regression analysis revealed that engagement in physical activity at baseline (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.23-3.08), smartphone ownership (OR = 2.15, 95% CI = 1.33-3.47), and visual impairment (OR = 1.79; 95% CI = 1.10-2.91) were independently associated with decreased physical activity during the COVID-19 emergency. Female respondents and smartphone ownership were significantly associated with more frequent handwashing. CONCLUSIONS: The study revealed that older adults in an urban setting responded to the COVID-19 emergency with behavioral changes. The findings of this study have implications for the design of preventive strategies to maintain the health and wellbeing of at-risk older adults.

Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with anticonvulsants in a Japanese population: Matched case-control and cohort studies.

BACKGROUND: Evidence for the risk and incidence of anticonvulsant-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Japan is scarce. METHODS: We conducted a matched case-control study using a large-scale Japanese claims database. SJS/TEN cases were identified using a claims-based algorithm developed in a previous study (sensitivity 76.9%, specificity 99.0%). Conditional logistic regression with Firth's bias correction to address an issue of rare events was used to estimate odds ratios (ORs) for SJS/TEN for each anticonvulsant use (90 days before the index date) versus non-use. 90-day cumulative incidence of SJS/TEN per 100,000 new users was calculated for 33 anticonvulsants. Causality between anticonvulsant use and SJS/TEN in each exposed case was assessed using the algorithm of drug causality for epidermal necrolysis (ALDEN) score. RESULTS: From 5,114,492 subjects, we selected 71 SJS/TEN cases and 284 controls. We observed significantly increased ORs for SJS/TEN among new users of carbamazepine (OR 68.00) and lamotrigine (OR 36.00) with ALDEN scores of "probable" or higher. Cumulative incidence of SJS/TEN was 93.83 for carbamazepine and 84.33 for lamotrigine. One case newly exposed to phenytoin which developed SJS/TEN was rated "unlikely" in ALDEN causality, resulting in cumulative incidence of 66.27. Cumulative incidence of SJS/TEN was 25.23 for levetiracetam, 7.52 for clonazepam, and 1.23 for diazepam, but their ALDEN scores were "very unlikely". CONCLUSIONS: This study is the first to document the differential risk of SJS/TEN for anticonvulsants in a real-world setting in Japan. Exposure to carbamazepine and lamotrigine was associated with an increased risk of SJS/TEN.

Lifestyle behaviors associated with the initiation of renal replacement therapy in Japanese patients with chronic kidney disease: a retrospective cohort study using a claims database linked with specific health checkup results.

BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for progression to an end-stage renal disease requiring dialysis or kidney transplantation. We investigated the association of lifestyle behaviors with the initiation of renal replacement therapy (RRT) among CKD patients using an employment-based health insurance claims database linked with specific health checkup (SHC) data. METHODS: This retrospective cohort study included 149,620 CKD patients aged 40-74 years who underwent a SHC between April 2008 and March 2016. CKD patients were identified using ICD-10 diagnostic codes and SHC results. We investigated lifestyle behaviors recorded at SHC. Initiation of RRT was defined by medical procedure claims. Lifestyle behaviors related to the initiation of RRT were identified using a Cox proportional hazards regression model with recency-weighted cumulative exposure as a time-dependent covariate. RESULTS: During 384,042 patient-years of follow-up by the end of March 2016, 295 dialysis and no kidney transplantation cases were identified. Current smoking (hazard ratio: 1.87, 95% confidence interval, 1.04─3.36), skipping breakfast (4.80, 1.98─11.62), and taking sufficient rest along with sleep (2.09, 1.14─3.85) were associated with the initiation of RRT. CONCLUSIONS: Among CKD patients, the lifestyle behaviors of smoking, skipping breakfast, and sufficient rest along with sleep were independently associated with the initiation of RRT. Our study strengthens the importance of monitoring lifestyle behaviors to delay the progression of mild CKD to RRT in the Japanese working generation. A substantial portion of subjects had missing data for eGFR and drinking frequency, warranting verification of these results in prospective studies.

Differences in efficacy evaluation endpoints in clinical trials for claiming reduction of post-prandial glycemic response between Japan and the European Union.

When evaluating the efficacy of foods with health claims (FHC), each country sets different standards for efficacy evaluation endpoints in clinical trials, which may result in a barrier, namely the case that the claim that is allowed in Japan cannot be used on the label in another region and vice versa. We aimed to investigate the efficacy evaluation endpoints used in clinical trials of FFCs containing ID and submitted in Japan, in reference to the EU requirements for substantiating the claim, namely "reduction of post-prandial glycemic responses". We detected only one difference in efficacy evaluation endpoints, which was insulin levels. We found 67 such clinical trials cited in systematic literature reviews on finished products or functional substance(s). Of these, 43 (64%) trials lacked insulin assessment. Particularly, for foods that were claimed to reduce post-prandial glycemic responses, the EU does not consider a claim to be substantiated unless insulin levels have been evaluated. Our findings suggest the need for standardization of requirements for FHC between Japan and the EU. This consideration will strengthen the evidence for clinical significance of ID and allow products labeled with this health claim to be more widely distributed.

Utility of a Specific Health Checkup Database Containing Lifestyle Behaviors and Lifestyle Diseases for Employee Health Insurance in Japan.

BACKGROUND: The Japanese Ministry of Health, Labour and Welfare introduced Specific Health Checkups (SHC) to identify individuals at risk of metabolic syndrome (MS). This study aimed to describe the SHC database developed by the Japan Medical Data Center Co., Ltd. (JMDC) as a means of exploring lifestyle behaviors and lifestyle diseases among working generations. METHODS: We conducted a retrospective, cross-sectional study of employees and their families using the JMDC-SHC database to describe the prevalence of lifestyle behaviors (smoking, exercise, dietary habits, drinking habits, and sleeping) and lifestyle diseases (MS, hypertension, dyslipidemia, and diabetes mellitus). Results were compared with data from the 2015 National Health and Nutrition Survey (NHNS) in Japan as a benchmark. RESULTS: All 646,869 enrollees in the JMDC-SHC database were included, of whom 66.5% were men. Age ranged from 40-74 years. Compared with the results of the NHNS, the JMDC-SHC subjects were younger and had fewer MS components and a lower prevalence of diabetes and hypertension. Subjects in their 40s were most likely to have unhealthy lifestyle behaviors in all age groups (eg, smoking: 41.0% in men and 10.2% in women). The SHC group had more favorable behaviors overall, but underweight was more prevalent in the SHC females. CONCLUSIONS: The JMDC-SHC population showed different lifestyle and lifestyle disease profiles to the NHNS population, probably due to its different age, gender, and employment distributions. Development of healthcare policies and plans for working generations would benefit from the selection of an age- and employment-appropriate database.

Medications and fall risk: a case-control study in nursing home residents in Japan.

AIM: Falls are a significant problem for older people, but are few studies of the risk of falling in residents of nursing homes in Japan. We aimed to investigate the risk factors for falls and the association of medication use and falls in nursing home residents in Japan. METHODS: This case-control study reviewed the records of residents of who were ≥ 65 years of age and had fallen in 2012 and an age-, sex-, and facility-matched control group selected from 58 nursing homes in Japan. The odds ratios of potential risk factors and current medications were determined by conditional logistic regression. RESULTS: A total of 1832 residents (916 cases and 916 controls) were included. Falls were significantly associated with an inability to walk without assistance or stand up without assistance, need for toileting assistance, visual impairment, insomnia, and dementia. Current prescription of antithrombotic, nonsteroidal anti-inflammatory, or antiparkinson drugs, muscle relaxants, antiepileptics, antipsychotics, antidepressants, opioids, selective serotonin reuptake inhibitors, and memantine was also associated with increased risk of falling. CONCLUSIONS: Many medications were associated with falls in nursing homes residents in Japan. To prevent these falls, caregivers should provide adequate care, and healthcare professionals should consider switching or dose reduction for these medications.

Correction to: Influenza vaccination effectiveness for people aged under 65 years in Japan, 2013/ 2014 season: application of a doubly robust method to a large-scale, real-world dataset.

After publication of the original article [1], in Table 1, in the second and third column, "Vacnee" and "Non-vacnee" should be replaced with "Vaccinee" and "Non-vaccinee".

Influenza vaccination effectiveness for people aged under 65 years in Japan, 2013/2014 season: application of a doubly robust method to a large-scale, real-world dataset.

BACKGROUND: Influenza vaccination is recognized as a primary public health intervention which prevents the illness of patients and relieves the societal burdens of influenza for medical community as well as the economy. To date, no effectiveness study of influenza vaccination has been conducted including a large population with a wide age span, in Japan. Here, we evaluated the clinical effectiveness of influenza vaccination in a large Japanese population. METHODS: We conducted a cohort study using a large-scale claims database for employee health care insurance plans. Vaccination status was identified using plan records for influenza vaccination subsidies. We excluded people aged 65 years or more because of the unavailability of vaccination records. Effectiveness of vaccination in preventing influenza and its complication was evaluated with doubly robust methods using inversed probability treatment weighting to adjust health conscious behaviours and other confounders. RESULTS: During the 2013/2014 influenza season, 369,425 subjects with age range from 1 to 64 years were eligible. Vaccination rate was 39.5% and an estimated odds ratio (OR) for influenza onset was 0.775 after doubly robust adjustment. Age-stratified ORs were significantly reduced in all age groups; lowest in subjects aged 1 to 4 years (0.600) and highest in those aged 13 to 19 (0.938). ORs for all the influenza complication outcomes were also statistically significant (0.403-0.709). CONCLUSIONS: We confirmed the clinical effectiveness of influenza vaccination in people aged 1 to 64 years. Influenza vaccination significantly prevented influenza onset and was more effective in reducing secondary risks of influenza complications.

[Effects of polypharmacy and anticholinergic/sedative drugs on the physical/cognitive/mental related outcomes of community-dwelling elderly people: The Kawasaki Wellbeing Project].

AIM: To assess the burdens of polypharmacy and the drug burden index in community-dwelling elder people. METHODS: The survey was conducted on 396 participants who participated in The Kawasaki Wellbeing Project from March to December 2017. We investigated the associations between the drug burden and the physical/cognitive/mental outcomes. The drug burden was determined by calculating the number of medications and the drug burden index (DBI) based on the use of anticholinergic and sedative drugs. A multivariate regression analysis was conducted for the outcome measures ADL, IADL, MMSE, J-CHS, and EQ5D5L after adjusting for the sex, age, number of diseases, education level, smoking history, and alcohol history. RESULTS: A total of 389 subjects were analyzed, the mean age of the population was 86 years old, and 187 people (48%) were male. Polypharmacy was reported in 243 people (62%), and DBI exposure was reported for 142 people (36.5%). We found that this population was physically healthy, with a median ADL of 100, and had high quality of life, with a median EQ5D5L of 0.895. Polypharmacy was found to be related to the J-CHS (ß: 0.04) and EQ5D5L (-0.01). The DBI was also related to the EQ5D5L (-0.04). CONCLUSION: These results showed that even though this population was healthier than the general Japanese elderly population, the drug burden of polypharmacy and high dosages of anticholinergic/sedative drugs exerted significant negative effects on frailty and the quality of life. Additional research should be conducted to investigate the long-term effects of polypharmacy and anticholinergic/sedative drugs on elderly people.

Persistence of oral antidiabetic treatment for type 2 diabetes characterized by drug class, patient characteristics and severity of renal impairment: A Japanese database analysis.

AIM: To evaluate the persistence with oral antidiabetic drug (OAD) treatment characterized by drug class, patient characteristics and severity of renal impairment (RI) in patients with type 2 diabetes (T2DM) in Japan. MATERIALS AND METHODS: This retrospective, observational study extracted data from a large-scale hospital database (April 2008 to September 2016). Patients with T2DM aged ≥40 years on the day of their first prescription (index date) of any OAD (biguanides [BGs], thiazolidinediones [TZDs], sulphonylureas [SUs], glinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, or α-glucosidase inhibitors [α-GIs]) available between January 1, 2014 and September 30, 2016 were identified. Sodium-glucose co-transporter-2 inhibitors were not available at study initiation. Treatment persistence was assessed by Kaplan-Meier survival curves. Patients were also categorized by RI status using estimated glomerular filtration rate: ≥90 mL/min/1.73 m2 (G1); 60 to <90 mL/min/1.73 m2 (G2); 30 to <60 mL/min/1.73 m2 (G3); and <30 mL/min/1.73 m2 (G4+). RESULTS: We identified 206 406 index dates from 162 116 eligible patients. The largest number of index dates (91634) was observed for DPP-4 inhibitors, followed by BGs, SUs, α-GIs, glinides and TZDs. Treatment persistence was longest for DPP-4 inhibitors (median 17.0 months, 95% confidence interval [CI] 16.4-17.5) and BGs (median 17.3 months, 95% CI 16.6-18.2), and shortest for α-GIs (median 5.6 months, 95% CI 5.4-5.9) and SUs (median 4.3 months, 95% CI 4.2-4.6). Persistence was longest with DPP-4 inhibitors at all RI stages (G1-G4+), followed by BGs at stages G1/G2. CONCLUSIONS: The longest OAD persistence was observed for BGs and DPP-4 inhibitors at RI stages G1/G2, and for DPP-4 inhibitors at RI stages G3/G4+.

Bridge the gap: The need for harmonized regulatory and ethical standards for postmarketing observational studies.

Drug safety issues do not respect national borders. Hence, addressing a safety question may necessitate globally coordinated efforts between regulatory authorities and market authorization holders (MAHs) to draw reliable conclusions. Regulatory authorities have shared responsibility with MAHs sponsoring postmarketing nonintervention studies in determining study goals and design. Their shared accountabilities include what will be investigated and how the data will be retrieved to ensure appropriate study quality required for regulatory decision making. The need for a harmonized framework and ethical standards for postmarketing observational studies is well recognized but has been lacking even among the United States, European Union, and Japan, which are so-called International Conference on Harmonisation (ICH) regions. A recent update of the Council for International Organizations of Medical Sciences International Ethical Guidelines for Health-Related Research Involving Humans provides further clarification on provisions for informed consent and the role of research ethics committees. However, without incorporation into legislative structures, the future impact of these guidelines is uncertain. This lack of harmonization leads to a complex and uncertain framework for ethical review and for participant informed consent, resulting in numerous inefficiencies in the regulatory postmarketing observational studies. The regulatory frameworks for postmarketing observational studies conducted under the auspices of regulatory agencies in the 3 regions are reviewed, with a focus on ethical requirements and opportunities for efficiencies.

The drug burden of anticholinergics and sedatives and influence on outcomes in the community-living oldest old: The Tokyo Oldest Old survey on Total Health (TOOTH) survey.

AIM: The objective of this study was to assess the burdens of anticholinergic and sedative drugs in community-living individuals of 85 years of age or older. METHODS: The Tokyo Oldest Old survey on Total Health (TOOTH) is a cohort study designed to assess the physical, mental, and oral health of the community-living oldest old. We investigated the relationships between the anticholinergic/sedative burden and physical/cognitive outcomes. The drug burden was assessed by the Drug Burden Index (DBI). Relationships between the DBI score and the physical/cognitive outcomes were evaluated by multivariate regression. The age-related changes (baseline to 3-year follow-up) of these outcomes were also investigated. RESULTS: At baseline, the data of 306 subjects were subjected to a cross-sectional analysis. The Instrumental Activities of Daily Living and Mini Mental State Examination scores were found to be significantly associated with the DBI score. After 3 years, the Activities of Daily Living score was significantly associated with the DBI score in 176 subjects. Changes in these outcome measures were small during the 3-year follow-up period and were not associated with the DBI scores at baseline. DISCUSSION: DBI in the community-living oldest old were evaluated. Our findings suggest that anticholinergic and sedative drugs may influence the physical and cognitive function in the oldest old. Additional studies should be performed to investigate the relationships between the change of the physical/cognitive functions and the DBI score over a long-term observation period.

Medications associated with falls in older people: systematic review of publications from a recent 5-year period.

PURPOSE: Falls are an important public health problem in older people. Medication use is considered a risk factor for falls. This study systematically reviewed recent studies to determine the medications that might be associated with the risk of falling in older people. METHODS: We conducted a systematic review of prospective and retrospective studies identified through the MEDLINE and CINAHL databases that quantitatively assessed the contribution of medications to falls risk in participants ≥60 years old published in English between May 2008 and April 2013. RESULTS: The search identified 1,895 articles; 36 articles met the inclusion criteria. Of the 19 studies that investigated the effect of polypharmacy on the risk of falling, six studies reported that the risk of falling increased with polypharmacy. Data on the use of antihypertensive medications including calcium channel blockers, beta-blockers, and angiotensin system blocking medications were collected in 14 studies, with mixed results. Twenty-nine studies reported an association between the risk of falls and psychotropic medications including sedatives and hypnotics, antidepressants, and benzodiazepines. CONCLUSIONS: The use of sedatives and hypnotics and antidepressants including tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors appears to be related with an increased risk of falls. It is not clear if the use of antihypertensive medications is associated with the risk of falls in older people.

Responsiveness of the Japanese Osteoporosis Quality of Life questionnaire in women with postmenopausal osteoporosis.

BACKGROUND: The Japanese Osteoporosis Quality of Life (JOQOL) questionnaire measures quality of life in Japanese patients with osteoporosis. However, several important aspects of the psychometric properties of individual domains, including responsiveness, have not been addressed to enable valid clinical application. This analysis examined the internal and external responsiveness of the JOQOL questionnaire. METHODS: This was a post hoc analysis of a 24-week prospective postmarketing study of raloxifene (60 mg/day) administered to postmenopausal Japanese women with osteoporosis (JapicCTI-070465). Internal responsiveness was assessed using Standardized Response Mean (SRM) statistics and changes in JOQOL domain scores. Patients were also stratified into those who did or did not achieve a minimal clinically important change (MCIC) in pain, assessed by a visual analogue scale for pain (VAS pain): comparisons were made between treated patients who achieved VAS pain reduction ≥ 20 mm versus VAS pain reduction < 20 mm. External responsiveness was assessed using Pearson's correlation coefficient (r) for changes in JOQOL domain scores with Short Form-8 Health Survey and European Quality of Life Instrument scores. RESULTS: Of 506 patients analyzed, 421 had a baseline value for VAS pain; of these, 152 patients (36.1%) had a MCIC, whereas 264 patients (62.7%) did not. The JOQOL domains pain, overall health, and falls/psychological factors had small to moderate SRM values (0.3-0.5) in all patients, but consistently showed significantly larger changes in patients whose pain score changes exceeded the MCIC. Together, these findings suggest some degree of internal responsiveness for these domains. However, activities of daily living domain had a SRM value as low as 0.2, and recreation/social activities and posture/physique domains had SRM values close to 0. Moderate correlation (defined as r ≥ 0.4 to < 0.6) was noted between the domains pain, activities of daily living, and overall health and some Short Form-8 Health Survey subscales and the European Quality of Life total score, suggesting external responsiveness of these domains. CONCLUSIONS: The inconsistent responsiveness among individual JOQOL domains in treated patients suggests the need for improving several JOQOL domains, especially the activities of daily living, recreation/social activities and posture/physique domains, before application to clinical research.

Comparison of Regulations for Arsenic and Heavy Metals in Herbal Medicines Using Pharmacopoeias of Nine Counties/Regions.

INTRODUCTION: Standardization is an import factor in ensuring the safety, efficacy, and quality of herbal medicines, and facilitates their international commerce. Heavy metal poisoning due to herbal medicines has been reported in many countries. Here, to better understand the current state of harmonization, we compared regulations for arsenic and heavy metals in herbal medicines across seven countries and two regions with two international standards. METHODS: We studied the monographs of herbal medicines of seven countries and two regions, as well as the WHO guidelines and ISO standards. We then compared the limits and test methods adopted for elemental impurities in herbal medicines listed in the monographs and standards among countries. RESULTS: The number of herbal medicines assessed amounted to over 2000. Limits and test methods adopted for elemental impurities in herbal medicines varied by country/region and organization. Although WHO recommends a uniform upper limit for lead and cadmium for all herbal medicines, some countries set unique upper limits for individual herbal medicines. ISO 18664:2015 lists only instrumental analysis methods, whereas Japan and India list only chemical methods. CONCLUSIONS: Many countries do not adhere to the WHO or ISO recommendations on elemental impurities in herbal medicines. These findings suggest the presence of differences in regulations for herbal medicines among countries/regions, likely rooted in cultural differences and policies aimed at maintaining the diversity of herbal medicines. Regulatory convergence by "loose harmonization" to internationally agreed standards appears a feasible option to maintain diversity and safety, and promote international trade in herbal medicines.

Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Associated With Antibiotic Use: A Case-Crossover Study.

BACKGROUND: Evidence is lacking on the association between antibiotic use and risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Asians. OBJECTIVE: We assessed the risk of SJS/TEN associated with different antibiotic classes in Japanese. METHODS: We conducted a case-crossover study using a claims database. Firth conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of SJS/TEN associated with antibiotic use in a 56-day hazard period versus 3 control periods. We created 18 cohorts for each antibiotic class and calculated 56-day cumulative incidence per 100,000 new users. The association between antibiotic class and SJS/TEN was also evaluated in each case using the ALgorithm of Drug causality for Epidermal Necrolysis (ALDEN). RESULTS: Our case-crossover study included 170 SJS/TEN cases. Increased ORs were observed for lincomycins (OR, 33.00 [95% CI, 3.74-4332.05]), trimethoprim-sulfamethoxazole (21.20 [6.73-105.98]), penicillins (14.39 [6.95-34.21]), glycopeptides (14.37 [3.17-136.10]), cephalosporins (7.06 [4.25-12.21]), aminoglycosides (6.55 [1.97-26.84]), quinolones (5.98 [3.34-11.20]), fosfomycin (5.40 [1.20-30.97]), carbapenems (5.09 [1.85-15.64]), tetracyclines (4.95 [1.78-15.27]), and macrolides (3.78 [2.13-6.83]). Cumulative incidence of SJS/TEN was 67.4 for trimethoprim-sulfamethoxazole, 86.2 for glycopeptides, and below 10.0 for the others. Despite the high incidence, only 2 cases had a probable causal relationship with glycopeptides. CONCLUSION: Some antibiotic classes, including lincomycins, glycopeptides, aminoglycosides, fosfomycin, and carbapenems, were newly suggested to be associated with risk of SJS/TEN; considered together with the high incidence for trimethoprim-sulfamethoxazole and glycopeptides, these findings warrant caution in clinical practice.

A quality management system aiming to ensure regulatory-grade data quality in a glaucoma registry.

BACKGROUND: Disease/patient registries are underutilized despite their multiple advantages over clinical trials in the clinical evaluation of drugs, such as the capacity for long-term curation, provision of patient outcome data in routine clinical practice, and provision of benchmark data for comparison. Ensuring the fit-for-purpose quality of data generated from such registries is important to informing regulatory decision making. Here, we report the construction of a quality management system aiming to ensure regulatory-grade data quality for a registry of Japanese patients with glaucoma to evaluate long-term patient outcomes. METHODS: The quality management system was established by reference to the risk-based approach in the ICH-E6 (R2) recommendations. The following three-component approach was taken: establishment of governance, computerized system validation (CSV), and implementation of risk assessment and control. Compliance of the system with the recommendations of regulatory guidelines relevant to use of the registry was assessed. RESULTS: Governance by academic collaboration was established. This was followed by the development of a total of 15 standard operating procedures, including CSV, data management, monitoring, audit, and management of imaging data. The data management system was constructed based on a data management plan, which specified data/paper flow and data management procedures. The electronic data capture (EDC) system was audited by an external vendor, and configured and validated using the V-model framework as recommended in the GAMP5 guideline. Informed consent, eligibility assessment and major ophthalmology measurements were determined as Critical to Quality (CTQ) factors. A total of 22 risk items were identified and classified into three categories, and operationalized in the form of a risk control plan, which included training sessions and risk-based monitoring. The glaucoma registry addressed most quality recommendations in official guidelines issued by multiple health authorities, although two recommendations were not met. CONCLUSIONS: We established and configured a quality management system for a glaucoma registry to ensure fit-for-purpose data quality for regulatory use, and to curate long-term follow-up data of glaucoma patients in a prospective manner.

Chromosomal variability of human mesenchymal stem cells cultured under hypoxic conditions.

Bone marrow derived human mesenchymal stem cells (hMSCs) have attracted great interest from both bench and clinical researchers because of their pluripotency and ease of expansion ex vivo. However, these cells do finally reach a senescent stage and lose their multipotent potential. Proliferation of these cells is limited up to the time of their senescence, which limits their supply, and they may accumulate chromosomal changes through ex vivo culturing. The safe, rapid expansion of hMSCs is critical for their clinical application. Chromosomal aberration is known as one of the hallmarks of human cancer, and therefore it is important to understand the chromosomal stability and variability of ex vivo expanded hMSCs before they are used widely in clinical applications. In this study, we examined the effects of culturing under ambient (20%) or physiologic (5%) O(2) concentrations on the rate of cell proliferation and on the spontaneous transformation of hMSCs in primary culture and after expansion, because it has been reported that culturing under hypoxic conditions accelerates the propagation of hMSCs. Bone marrow samples were collected from 40 patients involved in clinical research. We found that hypoxic conditions promote cell proliferation more favourably than normoxic conditions. Chromosomal aberrations, including structural instability or aneuploidy, were detected in significantly earlier passages under hypoxic conditions than under normoxic culture conditions, suggesting that amplification of hMSCs in a low-oxygen environment facilitated chromosomal instability. Furthermore, smoothed hazard-function modelling of chromosomal aberrations showed increased hazard after the fourth passage under both sets of culture conditions, and showed a tendency to increase the detection rate of primary karyotypic abnormalities among donors aged 60 years and over. In conclusion, we propose that the continuous monitoring of hMSCs will be required before they are used in therapeutic applications in the clinic, especially when cells are cultured under hypoxic conditions.