A Systematic Review of Treatment-Related Adverse Events for Combination Therapy of Multiple Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor.

BACKGROUND: Combination therapy with multiple tyrosine kinase inhibitors (multi-TKIs) and immune checkpoint inhibitors (ICIs) has been increasingly tested in clinical studies. This study aimed to investigate the effect of the addition of ICI to multi-TKIs on the profile of treatment-related adverse events. METHODS: An electronic database search was performed using PubMed and Web of Science to identify published clinical studies on multi-TKI monotherapy and multi-TKI plus ICI combination therapy from July 20, 2005 to July 1, 2023. The incidence rate of common adverse events caused by multi-TKI monotherapy and multi-TKI plus ICI combination therapy was obtained and compared from the viewpoints of (1) relative risk for the combination therapy vs sunitinib, (2) adverse event incidence rate by clinical trial, and (3) pooled incidence rate. The quality of the evidence was assessed with the Cochrane risk of bias tool. Meta-analysis used random effects models. RESULTS: This systematic review identified 83 clinical studies involving 7951 patients. The combination therapy of multi-TKI and ICI was associated with an increased risk of diarrhea (relative risk [RR]: 1.24, 95% confidence interval [CI]: 1.15-1.33, P < .001), hypothyroidism (RR: 1.44, 95% CI: 1.11-1.87, P = .0064) and rash (RR: 1.71, 95% CI: 1.18-2.47, P = .0045) compared with multi-TKI monotherapy. The addition of ICI was suggested to decrease the risk of adverse events related to performance status. CONCLUSION: Our study identified an increased risk of treatment-related adverse events associated with multi-TKI plus ICI combination therapy. This would help optimize the management of toxicities caused by multi-TKI plus ICI combination therapy.

Factors Associated with Inclusion of Japan in Phase I Multiregional Clinical Trials in Oncology.

BACKGROUND: Early inclusion of Japan in the global development program could be a key factor in reducing the drug lag, making participation in phase I multiregional clinical trials (Ph. I MRCTs) an important consideration for oncology drug development in Japan. We aimed to investigate the factors associated with the inclusion of Japan in Ph. I MRCTs in oncology. METHODS: We compared the trial design, target population, type of primary tested drug, trial conduct profile, and sponsor profile for Ph. I MRCTs with or without Japan conducted by the top 20 companies in more than two countries and started between January 1, 2011, and December 31, 2020. RESULTS: One hundred and ninety-seven Ph. I MRCTs included Japan, and 697 did not. Detailed features of the Ph. I MRCTs in oncology were summarized, and several factors (trial design, target population, trial conduct profile, and sponsor profile) associated with inclusion of Japan in the Ph. I MRCTs were identified. CONCLUSIONS: It is important for Japanese subsidiaries within global pharmaceutical companies to closely communicate with the headquarters based on medical practice and unmet needs in Japan to join global development from an early stage. In addition, further efforts to attract emerging biopharmaceutical companies to Japan from the regulatory and/or political perspectives would be needed, thereby preventing drug lag in Japan.

Characteristics of Anticancer Drugs Approved Under the Accelerated Approval Program in the US: Success or Failure in Converting to Regular Approval.

BACKGROUND: Accelerated approval (AA) program expedites access to promising drugs for life-threatening conditions, particularly in oncology. However, challenges arise from the trade-off between faster access and the certainty of clinical benefits. We examined the differences between the indications for successful conversion of AA to regular approval (RA) and those withdrawn from the perspective of whether the confirmatory trial was appropriately designed and conducted to verify the efficacy estimated in the pivotal trial for AA (AA trial). METHODS: All the anticancer drugs approved by the United States (US) Food and Drug Administration (FDA) between January 2016 and December 2019 were identified on the FDA website. From these, we selected drugs granted AA for solid tumors based on single-arm trials. We compared the characteristics of the AA and confirmatory trials between products that were successfully converted to RA and those that were withdrawn. RESULTS: Twenty-four AA indications were identified, of which 11 were converted to RA and 6 were withdrawn. The magnitude of the objective response rate (ORR) in both the AA and confirmatory trials was not a factor that clearly determined the conversion or withdrawal of AA. However, if the experimental arm did not achieve a certain level of ORR over the control arm in the confirmatory trial, it was thought to increase the uncertainty of successful conversion to RA. CONCLUSION: A relatively high ORR compared with that of the control arm in the confirmatory trial, after AA, is important for successfully obtaining RA.

Impact of the US Accelerated Approval for New Anticancer Drugs on Time to Verification of Benefit and Regulatory Approval in the EU and Japan.

The accelerated approval (AA) program in the USA has succeeded in expediting the regulatory approval of new cancer drugs based on surrogate endpoint data. It is unclear whether the AA program promotes overall drug development, including verification of the clinical benefit, as the verification of drugs granted AA often takes long time. To determine the impact of the AA program on overall drug development, the time required for verification of clinical benefits was compared between anticancer drugs that initially received AA and those that received regular approval (RA). It was found that anticancer drugs that were approved under the AA program took longer time for verification, suggesting that the program may delay the start of a confirmatory study, and there may be room for speeding up the process. In addition, discordance was found in the pivotal study between the USA and the EU and the USA and Japan for obtaining the indication for which AA was granted in the USA and a delay in the start of the confirmatory study for the AA indication was considered to lead to a delay in approval in the EU and Japan. Early initiation of confirmatory studies for AA indications is recommended to reduce the time that patients receive drugs with unproven benefit in the USA, as well as to deliver innovative new drugs to patients earlier in the EU and Japan.

Comparison of the Incidence of Adverse Events Between Japanese and Non-Japanese Healthy Subjects in Phase I Studies: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVE: Ethnic and racial differences are key factors affecting the results of clinical studies. However, the influence of these factors on the efficacy and safety of medicinal products remains unclear. Race-dependent nature is considered to be one of the factors causing differences in clinical findings, and we investigated its influence on the safety evaluation of drugs. METHODS: We searched PubMed and a Japan drug approval list to find relevant studies, and extracted phase I studies conducted with Japanese and non-Japanese participants using the same protocol and at the same study site. Pooled estimates of odds ratios (ORs) for the incidence of major adverse events in Japanese and non-Japanese participants were calculated, using a DerSimonian-Laird method with a random-effects model. RESULTS: Odds ratios for some adverse events in the active drug arm were significantly lower in Japanese participants: headaches [OR 0.65 (95% confidence interval [CI] 0.52-0.82), p = 0.0003], neurological disorders NEC [OR 0.70 (95% CI 0.53-0.93), p = 0.0135] in a High-Level Group Term, nervous system disorders [OR 0.64 (95% CI 0.49-0.82), p = 0.0004], infections and infestations [OR 0.71 (95% CI 0.53-0.95), p = 0.0202], and musculoskeletal and connective tissue disorders [OR 0.66 (95% CI 0.48-0.91, p = 0.0107] in the System Organ Class. CONCLUSIONS: Our research suggested that racial factors such as race-dependent nature influence a drug safety assessment. With knowledge of these differences, it is expected that Japan will actively conduct multi-regional clinical trials, in which more diverse populations are included.

Oncology drug lag in Japan: has it improved over the last decade?

BACKGROUND: Existing studies and statistics on the drug lag between Japan and the United States (US) for anti-cancer drugs indicate that it has decreased, whereas more drugs are left unapproved in Japan. This study aimed to quantify the impact of unapproved drugs on the drug lag. METHODS: Information on 136 anti-cancer drugs approved in the US between 2011 and 2022 was collected. The approval lag, defined as the number of days from the date of approval in the US to the date of approval in Japan, was calculated for all selected drugs, and the median was calculated using the Kaplan-Meier method. The approval lag for drugs not approved in Japan was treated as censored data. Factors potentially associated with the approval lag were explored using Cox regression analysis. RESULTS: The median approval lags for the first half-period (2011-2016) and the last half-period (2017-2022) were 961 days (2.6 years) and 1547 days (4.2 years), respectively (Log-rank test: p = 0.0687). The participation of Japan in the global pivotal trial was associated with a shorter approval lag, and new drug applications by non-Japanese companies that did not rank in the global sales top 20 were associated with a longer approval lag. CONCLUSIONS: Drug lag has not decreased over the last decade. The percentage of pivotal trials for US approval that included Japan has increased but should be further increased in the future. Japan may require a scheme to encourage smaller non-Japanese companies to include Japan in their global clinical development plan.

Decision and timing of safety-related labeling changes for new drugs in Japan: Comparison with the United States and the European Union.

PURPOSE: The aim of this study was to compare safety-related labeling changes for newly approved drugs in Japan with those in the United States (US) and the European Union (EU), where guidance on the details of pharmacovigilance (PV) process has been published, to examine the extent to which the Japanese PV process is working. METHODS: Safety-related labeling changes for new drugs approved within 1 year in Japan, the US, and the EU were reviewed for the number, timing, and concordance of contents of the labeling change between countries/region. RESULTS: The number of labeling changes and median time from approval to the change (min, max) were 57 cases and 814 (90, 2454) days in Japan, 63 cases and 852 (161, 3051) days in the US, and 50 cases and 851 (157, 2699) days in the EU. Distribution of the revision date of the concordant labeling change in the three countries/region and distribution of differences in revision date between the two countries/region showed no trend of delayed labeling change in a specific country/region. Concordance rate of the labeling change was 36.1% (30/83) in US-EU, 21.2% (21/99) in Japan-US, and 23.0% (20/87) in Japan-EU (Fisher's exact test, p = 0.0313 [Japan-US vs. US-EU], p = 0.066 [Japan-EU vs. US-EU]). CONCLUSIONS: There was no trend of fewer or later labeling changes in Japan compared to those in the US/EU. While the concordance rate in US-EU was low, that in Japan-US and Japan-EU were even lower. Further investigation is needed to understand the reasons for these differences.

Comparison of safety outcomes of anticancer drugs in Japanese and non-Japanese patients in multi-regional clinical trials: meta-analysis of safety profiles.

No report has assessed the differences in adverse event (AE) profiles of anticancer drugs for all types of cancers in clinical trials involving Japanese patients. This study aimed to compare the safety outcomes of anticancer drugs in Japanese and non-Japanese patients in multi-regional clinical trials (MRCTs), regardless of the type of cancer or drug. All new approvals of oncology drugs in Japan from January 2009 to December 2018 were searched through the Pharmaceuticals and Medical Devices Agency website. The odds ratio (OR) for comparing the incidence of AEs between Japanese and non-Japanese patients was estimated using the Mantel-Haenszel method with a random effect model. Sixty-six multi-regional phase 3 trials were identified involving 43,712 patients. Severe AE, AE leading to dose reduction, and AE leading to dose interruption were significantly more frequent in Japanese patients than in non-Japanese (odds ratios [ORs] were 1.32 (95% confidence interval (CI): 1.13-1.53), 1.97 (95% CI: 1.66-2.31), and 1.63 (95% CI: 1.43-1.86), respectively). Serious AEs (SAEs) and AEs leading to death were significantly less frequent in Japanese patients (OR: 0.70 (95% CI: 0.62-0.77) vs. 0.56 (95% CI: 0.44-0.67), respectively). There were no differences in AEs leading to study withdrawal. The incidence of most AEs was significantly higher in Japanese patients. In Japanese patients, the incidence of SAEs and AEs leading to death was low, but severe AEs, AEs leading to dose reductions, AEs leading to dose interruption, and individual adverse events were high.

Factors Related to Placebo Response in Randomized, Double-Blind Clinical Trials of Antidepressants in Children and Adolescents: A Meta-regression Analysis.

BACKGROUND AND OBJECTIVE: Many randomized clinical trials (RCTs) for antidepressants in children and adolescents have failed to demonstrate efficacy due to a high placebo response. The aim of this study was to identify the potential factors affecting placebo response using meta-regression analysis of RCTs for antidepressants in children and adolescents using the Children's Depressive Rating Scale-Revised (CDRS-R) as the outcome. METHODS: PubMed and ClinicalTrials.gov were searched for randomized, double-blind, placebo-controlled trials of antidepressants for the acute treatment of major depressive disorder in children and adolescents. The outcome used in the present study was the mean change of the CDRS-R total score from baseline to the last assessment for the primary efficacy in the placebo arm. Potential factors related to the placebo response, such as study design, operational, and patient factors, were explored using meta-regression. RESULTS: The analyses included 23 trials. On multivariable meta-regression, setting up a placebo lead-in period was significantly associated with a smaller placebo response in the CDRS-R. CONCLUSION: Setting up a placebo lead-in period should be considered in future clinical trials of antidepressants in adolescents and children.

Randomized controlled trial data for successful new drug application for rare diseases in the United States.

BACKGROUND: Randomized controlled trial (RCT) data have important implications in drug development. However, the feasibility and cost of conducting RCTs lower the motivation for drug development, especially for rare diseases. We investigated the potential factors associated with the need for RCTs in the clinical data package for new drug applications for rare diseases in the United States (US). This study focused on 233 drugs with orphan drug designations approved in the US between April 2001 and March 2021. Univariable and multivariable logistic regression analyses were conducted to investigate the association between the presence or absence of RCTs in the clinical data package for new drug applications. RESULTS: Multivariable logistic regression analysis showed that the severity of the disease outcome (odds ratio [OR] 5.63, 95% confidence interval [CI] 2.64-12.00), type of drug usage (odds ratio [OR] 2.95, 95% confidence interval [CI] 1.80-18.57), and type of primary endpoint (OR 5.57, 95% CI 2.57-12.06) were associated with the presence or absence of RCTs. CONCLUSIONS: Our results indicated that the presence or absence of RCT data in the clinical data package for successful new drug application in the US was associated with three factors: severity of disease outcome, type of drug usage, and type of primary endpoint. These results highlight the importance of selecting target diseases and potential efficacy variables to optimize orphan drug development.

Exploratory Analysis of Drug Lag in New Oncology Drugs Between Japan and the US.

BACKGROUND: Drug lag in Japan has greatly decreased over the past decades; however, new instances of drug lag have appeared along with changes in the circumstances of oncology drug development. We aimed to investigate the factors associated with the approval lag for new oncology drugs between Japan and the United States (US) over the past decade by comparing approval dates and modalities, lead indications, approval types, and phase I strategies for earlier approval in Japan. METHOD: We descriptively evaluated the characteristics of 117 new oncology drugs approved in either Japan or the US from January 1, 2011, to December 31, 2020. RESULTS: Seventy-one drugs were approved in Japan, 112 in the US, five only in Japan, and 46 only in the US. Interestingly, new oncology drugs were predominantly developed by the top 20 pharmaceutical companies in Japan; however, the opposite was true for drugs that were not yet approved in Japan. However, no clear trend was observed in the relationship between drug lag and the studied factors, except for the phase I strategy. There was a numerical but clear trend in which a higher percentage of phase I multiregional clinical trials (MRCTs) in the drug development strategy was observed for drugs with earlier approval in Japan. CONCLUSION: Participation in global drug development during the early stages, such as during phase I MRCTs, is one of the keys to successfully minimizing this new instance of drug lag in Japan.

Emergence of New Drugs for Intractable Diseases is Associated with an Increase in the Number of Patients Diagnosed Thereafter with Those Intractable Diseases.

BACKGROUND: Estimates of the prevalence of diseases can be affected by changes in the awareness of the diseases. The emergence of new drugs may affect the awareness of the diseases among patients and physicians. We have reported that the rate of increase in the number of drugs available was a statistically significant factor correlated with the rate of increase in the number of patients diagnosed thereafter. We aimed to investigate the impact of the emergence of new drugs on the number of patients diagnosed with individual intractable diseases and to determine the types of drugs that had a greater impact on these changes. METHODS: The number of patients, the number of drugs indicated and diagnostic and certification criteria for the diseases from 2004 to 2013 were collected from publicly available data. We compared the annual rate of increase in the number of patients before and after the emergence of new drugs. Factors affecting the annual rate of increase in the number of patients were investigated. RESULTS: The annual rate of increase in the number of patients was statistically significantly increased after the emergence of new drugs (Average increase of 0.9% per year, Wilcoxon signed-rank test; p = 0.035). The emergence of drugs with new active substances and drugs with new mechanisms of action were statistically significant factors correlated with the increase in the number of patients. CONCLUSION: The emergence of new drugs, especially drugs with new active substances and drugs with new mechanisms of action, was associated with an increase in the number of patients diagnosed thereafter.

[Association between Post-marketing Safety-related Regulatory Actions and Characteristics of New Drugs Approved in Japan between 2005 and 2016].

The pharmacovigilance activities of new drugs are usually planned and conducted based on the clinical safety information obtained at approval. Revealing pre- and post-marketing drug characteristics associated with post-marketing safety-related regulatory actions (PSRAs) would help facilitate pharmacovigilance activities as these activities are not sufficient for early detection of safety signals that require warning. Therefore, we investigated the association between PSRAs and characteristics of new drugs in Japan. New active substances approved in Japan between fiscal year 2005 and 2015 were analyzed. PSRAs were defined as "revisions of precautions in drug package insert" instructed by the regulatory authority within the first 5 years after the initial approval (up to 2021). Drug characteristics included therapeutic area, number of Japanese subjects in clinical trials, dose-response study in Japanese subjects, approval lag between Japan and the United States or Europe (US/EU), novelty of the drug, estimated number of target patients, and number of supplemental approvals. Negative binomial regression and path analyses were performed to investigate the association between PSRAs and drug characteristics. PSRAs were more common among antineoplastic agents and drugs with a larger estimated number of target patients and were less common among drugs with a longer approval lag between Japan and the US/EU. Supplemental approval was more common among antineoplastic agents, and there were fewer target patients for novel drugs. For new drugs with the characteristics identified in the present study, it is important to proactively collect post-market safety information by intensifying patient monitoring.

A Comparison of Safety Information in Drug Labeling at the Initial Approval of New Drugs Approved Both in Japan and the United States.

PURPOSE: Scientific information in the drug labeling is expected to be the most up-to-date and consistent information across countries where medicine is approved. The objective of the present study is to investigate the consistency of safety-related information on product labeling for novel therapeutics concurrently approved in Japan and the US. METHODS: Safety information at the time of initial approval of new drugs approved concurrently both in Japan and the US in the recent 7 years were identified and reviewed for concordance. Factors associated with the discordance were also investigated. RESULTS: Despite the similar medical practices, population health, and regulation in Japan and the US, the level of concordance of safety information found in the drug labeling of 45 new active substances was low (20.4%). The development strategy of the drugs and having the same MAH were significantly associated with the concordance rate. The mean concordance rate among the 9 drugs with Black Box Warning in both countries was also low (32.9%). CONCLUSIONS: We found a low level of concordance between Japan and the US even when related to clinically important information raised by Black Box Warnings. The low concordance rate highlighted the need for a greater transparency in decision-making processes about the safety information in a drug labeling by both industry and regulators to take appropriate countermeasures against the discordance.

Combinations of Drug Candidate Properties Affecting Development Success and Discontinuation for 5 Diseases: Lymphoma, Non-Small Cell Lung Cancer, Arthritis, Depression, and Alzheimer Disease.

The effects of the properties of drug candidates on their successful approval for the treatment of diseases are substantial. However, the success rate of candidates when their properties are combined has not been sufficiently evaluated. We aimed to identify combinations of properties (target, action, and modality) that increased the approval success rate of drug candidates for 5 diseases as well as to understand the characteristics of discontinued candidates. We calculated the approval success rates by combining the properties of drug candidates developed for 5 diseases (non-small cell lung cancer, lymphoma, arthritis, depression, and Alzheimer disease [AD]), using candidates for which clinical development was initiated between 2000 and 2010. We also analyzed the phases and the reasons for the discontinuation of candidates of the 5 diseases for which development was discontinued. Probable combinations of properties with relatively high success rates for the diseases except for Alzheimer disease were found. These combinations of properties were considered appropriate in light of the pathology of each disease. The percentage of candidates discontinued in phase III for Alzheimer disease was higher than that for the other diseases. The reasons for discontinuation showed different trends between combinations of properties that had high and low approval success rates. As the effects of the properties of candidates on the success rate vary depending on the intended disease, pharmaceutical companies need to consider the probability of success of candidates for individual diseases for more efficient candidate selection.

Randomized Controlled Trial Data for New Drug Application for Rare Diseases in Japan.

BACKGROUND: High-quality evidence is often not obtained in the clinical trials of rare diseases because these trials tend to be smaller in size and non-controlled. We investigated the potential factors associated with the need for randomized controlled trials (RCTs) in the clinical data package for new drug applications for rare diseases in Japan. METHODS: This study focused on 130 drugs with orphan drug designation approved in Japan between April 2004 and March 2020. RESULTS: Multivariable regression analysis showed that the prevalence (odds ratio [OR] 3.21, 95% confidence interval [CI] 1.18-8.6) and the type of primary endpoint (OR 6.66, 95% CI 2.41-18.37) were associated with the need for RCTs in the clinical data package in Japan. CONCLUSIONS: Our findings highlight the importance of adequate understanding of the target disease in new drug development for rare diseases.

Impact of the Economic Status of the Patient's Country of Residence on the Outcome of Oncology Clinical Trials.

BACKGROUND: Prolongation of overall survival (OS) is commonly evaluated as a primary endpoint in confirmative oncology clinical trials; however, it is potentially affected by subsequent treatments carried out in practice. To design and implement multi-regional clinical trials properly, we compared survival outcomes between Organisation for Economic Co-operation and Development (OECD) and non-OECD countries. MATERIALS AND METHODS: Individual patient data from industry-sponsored multi-regional phase III oncology trials were obtained from the Project Data Sphere. Patients of each arm were divided into several subgroups based on race and country where patients were enrolled. We defined the member countries of the OECD. Cox regression analysis was conducted to estimate the hazard ratio (HR) for progression-free survival (PFS) and OS between the different subgroups in each trial, followed by a meta-analysis to estimate the summary HR and its confidence interval with a random-effect model. RESULTS: Eleven arms from 10 clinical trials were eligible for the analysis. No statistically significant difference was observed in PFS and OS between Caucasian and Asian. A prolongation of OS was observed in patients enrolled in the OECD group compared with non-OECD group, while no statistically significant difference was observed in PFS. CONCLUSION: The economic status and healthcare environment of countries where patients reside have an impact on the outcome of OS. Clinical trial sponsors are recommended to consider carefully how to properly design oncology clinical trials including the selection of countries and data management of subsequent treatments.

Response rate of anticancer drugs approved by the Food and Drug Administration based on a single-arm trial.

BACKGROUND: In recent years, an increasing number of anticancer drugs have been approved based on the results of a single-arm trial (SAT). The magnitude of the objective response rate (ORR) in SATs is important for regulatory decisions, but there has been no clear guidance specifying the degree of ORR for approval. METHODS: All anticancer drugs approved by the US Food and Drug Administration (FDA) between January 2016 and December 2019 were identified through the FDA website. From these, we selected drugs approved for solid tumors based on SATs. For each indication, one regimen was selected from the standard-of-care as the best comparison therapy (BCT), which was defined as the latest regimen for the same tumor and treatment line. We compared the ORR of the investigated product with that of the BCT. RESULTS: Of the 31 solid tumor indications identified, we selected BCT for 28. In 23 of the 28 indications (82.1%), the ORR of the investigated product exceeded that of the BCT, and in 16 of these (69.6%), the lower limit of the 95% confidence interval (CI) of the ORR of the investigated product exceeded the point estimate of the BCT ORR. For seven products, the lower limit of the 95% CI was below the point estimate of the BCT ORR, with differences ranging from 1.0% to 3.4%. CONCLUSION: The lower limit of a 95% CI of the ORR of a new drug in an SAT exceeding the point estimate of the BCT ORR could be an important factor in obtaining regulatory approval.

Acceptability of Manufacturer-Proposed Utility Values for NICE Cancer Medicine Appraisals: Analysis of Manufacturers' Information Sources.

OBJECTIVES: The National Institute for Health and Care Excellence's (NICE) method guide for technology appraisals (TAs) encourages medicine manufacturers to use the EuroQol 5 Dimensions (EQ-5D) in relevant clinical trials to obtain utility values; however, the EQ-5D may have low sensitivity when compared to disease-specific measures. This study investigated whether the NICE TA committee's acceptance of manufacturer-proposed utility values is dependent on the manufacturers' sources of the utility values. METHODS: Using publicly available data for 2011-2020, we identified 136 single TAs of cancer medicines, the health-related quality-of-life-measures used in relevant clinical trials, manufacturers' sources of utility values, and the NICE TA committee's acceptance of these values. Fisher's exact tests were performed to compare the acceptability of different value sources and reasons for non-acceptance. RESULTS: The number of appraisals for which the EQ-5D in the relevant clinical trials was the source of the manufacturer-proposed utility values increased continuously over time. The TA committee's acceptance of values was not dependent on the information source. In cases where a submission for which the information source was the EQ-5D was rejected, the reason was generally related to inappropriate values for the UK population or inappropriate data adjustment, not data reliability. CONCLUSIONS: Our results demonstrated that according with the NICE's method guide regarding utility values does not guarantee acceptance by the TA committee. Manufacturers must consider in advance possible differences between their clinical trials and clinical practice in the UK and refine plans for EQ-5D measurement in order to obtain convincing evidence.

Estimation of the Under-Reporting of Suspected Serious Adverse Drug Reactions in Japan Using An Interrupted Time Series Analysis.

OBJECTIVE: Spontaneous reports of adverse drug reactions (ADRs) are an essential data source for pharmacovigilance activities. However, spontaneous reporting is affected by under-reporting, which can lead to bias in statistical signal detection and failure to identify potential drug-associated risks. This study aimed to estimate the degree of under-reporting of suspected serious ADRs (sADRs) in spontaneous reports in Japan. METHODS: The new active ingredients approved in Japan between 2010 and 2016 for which all-case surveillance was conducted were selected for this study. Data of sADR reports were extracted from the Japanese Adverse Drug Event Report database (JADER). An interrupted time series (ITS) analysis was conducted to compare the number of sADR reports (sADR cases) obtained in the all-case surveillance period with that obtained in the spontaneous report period (after all-case surveillance had been completed). RESULTS: The ITS analysis of all sADR cases revealed that 24 (68.6%) of the 35 investigated drugs showed a statistically significant decrease in the intercept (level) in the spontaneous reporting period compared with that in the all-case surveillance period. The median of the reduction rate of the level was 60.1%. The number of drugs with a statistically significant decrease in the level of cases with sADRs in the Important Medical Event list and in that leading to death was 19/35(54.3%) and 6/35 (17.1%), respectively. CONCLUSION: This study demonstrated the existence of sADR under-reporting in spontaneous reports in Japan quantitatively. Meanwhile, it was suggested that information on sADRs was reported appropriately according to their level of severity.