Approvals of type 2 diabetes drugs tested in cardiovascular outcome trials: A tripartite comparison.

AIMS: In 2008, the US Food and Drug Administration (FDA) issued a guidance requiring that cardiovascular outcome trials (CVOTs) be conducted for newer hypoglycaemic drugs for type 2 diabetes (T2D). We aimed to examine the decisions by 3 regulatory authorities in response to identical CVOT data. METHODS: We surveyed ClinicalTrials.gov to identify CVOTs and examined the revision histories of drug labels in databases from the FDA, the European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan. RESULTS: We selected 14 drugs and corresponding CVOTs, 12 of which were conducted as postmarketing trials. In the USA and the EU, the pre-CVOT indication on all 14 labels was "improvement in glycaemic control". Six drugs showed significant cardiovascular risk reduction, which led to an additional indication regarding reduction of cardiovascular adverse events in the USA, and a change to the EU indication to specify treatment of adults with T2D. The initial indication in Japan, T2D, remained unchanged. Regarding safety, significant increases in heart failure were observed only in the saxagliptin trial. A warning was added to the saxagliptin labels in the EU and Japan, whereas the FDA required a class effect warning to be added to the labels of all 4 dipeptidyl peptidase-4 inhibitors. CONCLUSIONS: Regulatory authorities using identical trial data made substantially different decisions regarding both safety and efficacy of hypoglycaemic drugs. The differences in initial indication wording between Japan and the other authorities suggest that trial data and T2D are interpreted differently in these regions.

Guidance for peptide vaccines for the treatment of cancer.

Recent progress in fundamental understanding of tumor immunology has opened a new avenue of cancer vaccines. Currently, the development of new cancer vaccines is a global topic and has attracted attention as one of the most important issues in Japan. There is an urgent need for the development of guidance for cancer vaccine clinical studies in order to lead to drug development. Peptide vaccines characteristically have the effect of indirectly acting against cancer through the immune system - a mechanism of action that clearly differs from anticancer drugs that exert a direct effect. Thus, the clinical development of cancer peptide vaccines should be planned and implemented based on the mechanism of action, which differs significantly from conventional anticancer drug research. The Japanese Society for Biological Therapy has created and published Guidance for peptide vaccines for the treatment of cancer as part of its mission and responsibilities towards cancer peptide vaccine development, which is now pursued globally. We welcome comments from regulators and business people as well as researchers in this area.

Conflicts of interest in psychiatry: strategies to cultivate literacy in daily practice.

The relationship between psychiatry and pharmaceutical companies has come under scrutiny during the past decade. Concerns are growing that financial ties of psychiatrists to the pharmaceutical industry may unduly influence professional judgments involving the primary interests of patients. Such conflicts of interest threaten the public trust in psychiatry. The goal of conflict of interest policies is to protect the integrity of professional judgment and to preserve public trust. The disclosure of individual and institutional financial relationships is a critical but limited first step in the process of identifying and responding to conflicts of interest. Conflict of interest policies and procedures can be strengthened by engaged psychiatrists, researchers, institutions, and professional associations in developing policies and consensus standards. Research on conflicts of interest can provide a stronger evidence base for policy design and implementation. Society has traditionally granted the medical profession considerable autonomy and may be willing to continue do so in the case of conflicts of interest. Nevertheless, concern is growing that stronger measures are needed. To avoid undue regulatory burdens, psychiatrists can play a vital role in designing responsible and reasonable conflict of interest policies that reduce the risks of bias and the loss of trust. Psychiatrists and the institutions that carry out research, education, clinical care, and practice guideline development must recognize public concerns about conflicts of interest and take effective measures soon to maintain public trust with a cultural change in the practice of psychiatry, from reactive treatment-seeking for mental illness to proactive advocacy for patients.

Safety information in drug labeling: a comparison of the USA, the UK, and Japan.

PURPOSE: Despite globalization of drug approvals, there is a disparity in drug safety regulations among the USA, Europe, and Japan. We sought to determine differences in safety information on drug labels among the three regions. METHODS: This was a cross-sectional study with quantitative survey of safety information on labels of 189 new molecular entities approved in the USA, the UK, and Japan. Outcome measures were the proportions of total safety information (PSI), of contraindications (PCI), and of boxed warnings (PBW) to all information on the label. We identified a boxed warning (BW) on US and Japanese labels through a manual search. These measures were analyzed according to therapeutic indications. RESULTS: On the Japanese labels, PSI was smaller than that on the US and UK labels for cardiovascular diseases. For neoplastic and immunologic diseases, PSI on the Japanese labels was larger than that on the UK labels. For nervous system diseases, PSI on the US labels was larger than that on the UK and the Japanese labels. PCI showed contrasting results with PSI except for neoplastic and immunologic diseases. BWs showed a poorer concordance between the USA and Japan in hematologic and genitourinary diseases than in other therapeutic areas. CONCLUSIONS: Substantial differences in safety information exist depending upon outcome measures and therapeutic areas among the US, the UK, and the Japanese labels. This underscores the need for further analyses to determine causes of these differences to optimize drug safety regulations.

Potential adverse events in Japanese women who received tozinameran (BNT162b2, Pfizer-BioNTech).

Reports of cerebral venous sinus thrombosis and intracranial hemorrhage (ICH) following the administration of coronavirus vaccines have raised concerns regarding their safety. Although no regulatory authority has recognized ICH as an adverse event associated with tozinameran (BNT162b2, Pfizer-BioNTech), fatal and non-fatal cases have been reported. In Japan, 10 fatal cases (five men and women) have been reported to date. Four of the five women died of ICH and the other died of aspiration pneumonia, whereas all five men died of causes other than stroke. This imbalance is incompatible with the mortality data on cardiovascular diseases in the National Statistics, which show no apparent disparity between sexes or between hemorrhagic and ischemic stroke. Cumulatively, our analysis reveals a disproportionately high incidence of death by ICH in Japanese women who received tozinameran, suggesting a potential association of ICH with the vaccine. Although we understand that the benefits of tozinameran still outweigh the risks, we believe that a causal link with the vaccine is not proven but possible and warrants further analysis.

Regulatory perspectives on next-generation sequencing and complementary diagnostics in Japan.

INTRODUCTION: The 'one biomarker/one drug' scenario is unsustainable because cancer is a complex disorder that involves a number of molecular defects. In the past decade, major technological advances have lowered the overall cost and increased the efficiency of next-generation sequencing (NGS). AREAS COVERED: We review recent regulations on NGS and complementary diagnostics in Japan, mainly focusing on high-quality studies that utilized these new diagnostic modalities and were published within the last 5 years. We highlight significant changes in regulation, and explain the direction of efforts to translate the results of NGS and complementary diagnostics into clinical practice. EXPERT OPINION: NGS holds a number of advantages over conventional companion and complementary diagnostics that enable simultaneous analyzes of multiple cancer genes to detect actionable mutations. Parallel technological developments and regulatory changes have led to the rapid adoption of NGS into clinical practice. NGS-based genomic data have been leveraged to better understand the characteristics of a disease that affects its patient's response to a given therapy. As NGS-based tests become more widespread, however, Japanese authorities will face significant challenges particularly with respect to the complexity of genomic data, which will have to be managed if NGS is to benefit patients.

Efficient synthesis of 3-arylphthalides using palladium-catalyzed arylation of aldehydes with organoboronic acids.

The synthesis of 3-arylphthalides via palladium-catalyzed arylation of aldehydes with organoboronic acids was achieved using the thioether-imidazolinium carbene ligand in good to excellent yields and was carried out using 1.0 mol % of the catalyst with high substrate tolerance.

Imbalance in glycemic control between the treatment and placebo groups in cardiovascular outcome trials in type 2 diabetes.

BACKGROUND: Glycated hemoglobin (HbA1c) is accepted as the most reliable marker for assessing chronic glycemia. The present study aimed to investigate glycemic control in cardiovascular outcome trials (CVOTs) performed by pharmaceutical sponsors, at the request of the United States Food and Drug Administration (FDA) to ensure that newer hypoglycemic agents do not increase cardiovascular risk for patients with type 2 diabetes. METHODS: We chose ClinicalTrials.gov as a data source to identify randomized, double-blind, placebo-controlled non-inferiority trials of newer hypoglycemic agents for which the FDA 2008 guidance required a CVOT involving patients with type 2 diabetes. RESULTS: We identified 12 CVOTs, all of which were performed in accordance with the FDA guidance and published as of December 2018. Participants received either active treatment or placebo in addition to their existing therapy. On the assumption that HbA1c concentrations would be higher in the placebo group than in the treatment group, the use of open-label glucose lowering agents was encouraged as required to help all patients reach appropriate HbA1c targets according to local guidelines. As a result, the number of patients who received additional hypoglycemic agents during the trial was greater in the placebo group than in the treatment group in 10 of the CVOTs. Although the CVOTs were designed to avoid any imbalance in glycemic control between the groups, HbA1c concentrations were substantially higher in the placebo group than in the treatment group in all CVOTs throughout the observational period. The inferior glycemic control in the placebo groups was not considered in analyzing the outcomes in any of the CVOTs. CONCLUSIONS: The safety and efficacy of new hypoglycemic agents are potentially inflated because the participants in the placebo groups unexpectedly exhibited inferior glycemic control throughout the trial compared with the outcomes in the treatment groups. This imbalance may distort data interpretation and mask potential risks of the drugs. Re-analysis with adjustment for HbA1c concentrations would determine whether the results of these CVOTs were biased by the difference in glycemic control between the treatment and placebo groups and reveal potential effects of the test drugs independent of glycemic control.

Challenges to hemoglobin A1c as a therapeutic target for type 2 diabetes mellitus.

Glycated hemoglobin (HbA1c) is widely accepted as the most reliable measure of long-term glycemia. However, there is disagreement among professional medical societies on a proper glycemic target for long-term benefits in type 2 diabetes (T2D). The use of some glucose-lowering drugs was associated with heart failure despite substantial lowering of HbA1c. The failure of intensive glycemic control to reduce cardiovascular risk in some trials again brought into question the usefulness of HbA1c as a therapeutic target in T2D. In large cardiovascular outcome trials, some newer glucose-lowering drugs were associated with higher risks of heart failure or amputation despite comparable glycemic control between the test and placebo groups. Here, we provide evidence that variation in hemoglobin glycation between individuals is responsible for these inconsistencies. We suggest that further research be conducted in this area and that the findings be applied to clinical trials and practice.

Palladium-catalyzed 1,2-addition of potassium aryl- and alkenyltrifluoroborates to aldehydes using thioether-imidazolinium carbene ligands.

Palladium-catalyzed 1,2-addition of potassium aryl- and alkenyltrifluoroborates to aldehydes using thioether-imidazolinium carbene ligands proceeded readily under aqueous conditions. This process tolerated a diverse range of potassium trifluoroborate salts and aldehydes, giving a variety of carbinol derivatives with good to excellent yields.

Design and synthesis of N-alkyl oxindolylidene acetic acids as a new class of potent Cdc25A inhibitors.

The oxindolylidene acetic acids having long N-alkyl chains exhibited strong inhibitory activity toward dual specificity phosphatase Cdc25A.

Natural language processing-based assessment of consistency in summaries of product characteristics of generic antimicrobials.

To investigate consistency in summaries of product characteristics (SmPCs) of generic antimicrobials, we used natural language processing (NLP) to analyze and compare large amounts of text quantifying consistency between original and generic SmPCs. We manually compared each section of generic and original SmPCs for antimicrobials listed in the electronic Medicines Compendium in the United Kingdom, focusing on omissions and additions of clinically significant information (CSI). Independently, we quantified differences between the original and generic SmPCs using Kachako, a fully automatic NLP platform. Among the 137 antimicrobials listed in the electronic Medicines Compendium, we identified 193 pairs of original and generic antimicrobial SmPCs for the 48 antimicrobials for which generic SmPCs existed. Of these 193 pairs, 157 (81%) were consistent and 36 were inconsistent with the original SmPC. When the cut-off value of RATE (the index of similarity between two SmPCs) was set at 0.860, our NLP system effectively discriminated consistent generic SmPCs with a specificity of 100% and a sensitivity of 61%. We observed CSI omissions but not additions in the SmPC subsection related to pharmacokinetic properties. CSI additions but not omissions were found in the subsections dealing with therapeutic indications and fertility, pregnancy and lactation. Despite regulatory guidance, we observed substantial inconsistencies in the information in the United Kingdom SmPCs for antimicrobials. NLP technology proved to be a useful tool for checking large numbers of SmPCs for consistency.

Approval status and evidence for WHO essential medicines for children in the United States, United Kingdom, and Japan: a cross-sectional study.

BACKGROUND: The WHO Model List of Essential Medicines for Children (EMLc) covers medicines for globally high-burden diseases. Regulatory approval in high-income countries ensures evidence and dosage form but usually focuses on diseases common in those countries and not in low- and middle-income countries. METHODS: This cross-sectional study assessed supporting evidence for the 346 medicines in the 5th WHO EMLc and their approval data from the United States, United Kingdom, and Japan. RESULTS: Of the 346 EMLc medicines, 307 were approved in one or more of the three countries, 278 of which had supporting evidence of efficacy. The percentage of medicines approved in one or more of the three countries was lowest for antiparasitics (60%) whereas 100% for medicines for cancers and musculoskeletal and respiratory conditions were approved. Five of the 30 EMLc antineoplastics had no supporting paediatric evidence. Of the 39 EMLc medicines unapproved in all three countries, 26 were indicated for neglected infectious diseases (NIDs). Ten of the 26 had supporting paediatric evidence. Seventeen of the 39 unapproved medicines had no paediatric dosage form available, and all 17 were indicated for NIDs. CONCLUSIONS: Most EMLc medicines for diseases common in the three countries had supporting evidence, which was closely associated with approval, whereas a substantial number of medicines for NIDs were unapproved in the three countries, regardless of whether they had supporting evidence. Because of the limited contribution to the EMLc from high income countries, appropriate incentive mechanisms for pharmaceutical companies are required to make paediatric development for NIDs feasible and effective.

Overcoming regulatory challenges in the development of companion diagnostics for monitoring and safety.

Concurrent development and co-approval of a companion diagnostic (CDx) with a corresponding drug is ideal, but often unfeasible. Because of limited exposure to a drug in clinical trials, crucial information on safety is sometimes revealed only after approval. Therefore, a CDx for monitoring/safety is often developed after approval of a corresponding drug. However, regulatory guidance is insufficient if contemporaneous development is not possible, thereby leaving plenty of opportunities for improvement with respect to pharmacovigilance and retrospective validation of the CDx. Furthermore, global harmonization of guidance on how to incorporate new scientific information from retrospective analyses of biomarkers should lead to the establishment of more evidence for the development of CDx for approved drugs.

Drug-diagnostic co-development: challenges and issues.

Diagnostic tests have become increasingly important for optimizing drug use. Ideally, a companion diagnostic test is developed concurrently with a corresponding therapeutic product (co-development). However, the diagnostic test may also be developed to optimize treatment with previously approved therapeutic agents (follow-up-development). In co-development, the effectiveness of an agent in marker-defined patients is confirmed by an enrichment trial design. In follow-up-development, a biomarker is validated by prospective and/or retrospective analyses of unselected design trials. A prospectively designed trial is the gold-standard approach to biomarker validation, but retrospective validation can be used to efficiently determine effective treatments for marker-defined patients. Accumulation and systematization of examples of drug-diagnostic development will aid in the effective development of companion diagnostics.

International differences in companion diagnostic approvals: how are we able to manage the differences?

One would expect regulations for drugs and diagnostics not to differ significantly between countries, given that regulatory authorities evaluate the same scientific data generated in an increasingly globally harmonized context. However, studies of our own and others have provided compelling evidence of differences in regulations for drugs and in vitro companion diagnostics in personalized medicine. Differing regulatory processes create hurdles for both pharmaceutical and companion diagnostics companies with different platforms that employ different technologies. The rising cost of healthcare caused by improvements in technology is another issue that faces all advanced countries. To address these issues and to facilitate access to personalized medicine, regulatory authorities, academia and the pharmaceutical industry should increase dialogue on the differences on an international platform.