[Efficacy of TAS-102].

Of late, there has been rapid development of chemotherapeutic agents for treating metastatic colorectal cancers. However, the so-called "druglag" is a long-standingproblem; it refers to the drugapproval delays in Japan that occur after drugs have been developed and approved in Europe and the USA. Clinical trials for the drugTAS -102 were stopped in the USA, but the drugwas evaluated in phase I and II clinical trials in Japan. The Phase II trial for TAS-102 in Japan provided positive results, and it received approval in Japan first, ahead of the world. Data from the global phase III RECOURSE trial were presented in the ESMO-GI 2014, where the efficacy of TAS-102 was proved again. Herein, we present data about the efficacy and side effects of TAS-102 from each clinical trial.

Evaluating the risks of clinical research: direct comparative analysis.

OBJECTIVES: Many guidelines and regulations allow children and adolescents to be enrolled in research without the prospect of clinical benefit when it poses minimal risk. However, few systematic methods exist to determine when research risks are minimal. This situation has led to significant variation in minimal risk judgments, raising concern that some children are not being adequately protected. To address this concern, we describe a new method for implementing the widely endorsed "risks of daily life" standard for minimal risk. This standard defines research risks as minimal when they do not exceed the risks posed by daily life activities or routine examinations. METHODS: This study employed a conceptual and normative analysis, and use of an illustrative example. RESULTS: Different risks are composed of the same basic elements: Type, likelihood, and magnitude of harm. Hence, one can compare the risks of research and the risks of daily life by comparing the respective basic elements with each other. We use this insight to develop a systematic method, direct comparative analysis, for implementing the "risks of daily life" standard for minimal risk. The method offers a way of evaluating research procedures that pose the same types of risk as daily life activities, such as the risk of experiencing anxiety, stress, or other psychological harm. We thus illustrate how direct comparative analysis can be applied in practice by using it to evaluate whether the anxiety induced by a respiratory CO2 challenge poses minimal or greater than minimal risks in children and adolescents. CONCLUSIONS: Direct comparative analysis is a systematic method for applying the "risks of daily life" standard for minimal risk to research procedures that pose the same types of risk as daily life activities. It thereby offers a method to protect children and adolescents in research, while ensuring that important studies are not blocked because of unwarranted concerns about research risks.

A multivariate approach linking reported side effects of clinical antidepressant and antipsychotic trials to in vitro binding affinities.

The vast majority of approved antidepressants and antipsychotics exhibit a complex pharmacology. The mechanistic understanding of how these psychotropic medications are related to adverse drug reactions (ADRs) is crucial for the development of novel drug candidates and patient adherence. This study aims to associate in vitro assessed binding affinity profiles (39 compounds, 24 molecular drug targets) and ADRs (n=22) reported in clinical trials of antidepressants and antipsychotics (n>59.000 patients) by the use of robust multivariate statistics. Orthogonal projection to latent structures (O-PLS) regression models with reasonable predictability were found for several frequent ADRs such as nausea, diarrhea, hypotension, dizziness, headache, insomnia, sedation, sleepiness, increased sweating, and weight gain. Results of the present study support many well-known pharmacological principles such as the association of hypotension and dizziness with α1-receptor or sedation with H1-receptor antagonism. Moreover, the analyses revealed novel or hardly investigated mechanisms for common ADRs including the potential involvement of 5-HT6-antagonism in weight gain, muscarinic receptor antagonism in dizziness, or 5-HT7-antagonism in sedation. To summarize, the presented study underlines the feasibility and value of a multivariate data mining approach in psychopharmacological development of antidepressants and antipsychotics.

New rules for clinical trial-related injury and compensation.

The rules for compensation for injury and death in clinical trials have recently been notified. These rules clarify that medical management of all injuries in clinical trials is mandatory and in cases in which injury or death is related to the clinical trial, the subject (or nominee) is entitled to compensation over and above the medical management. They also specify procedures and timelines for reporting serious adverse events. These require simplification. The rules will hopefully make clinical trial safer for subjects and investigators alike. However, they suffer from certain inconsistencies that should be reconsidered. They need to be modified so that they do not damage the industry.

Comparative mortality risk in adult patients with schizophrenia, depression, bipolar disorder, anxiety disorders, and attention-deficit/hyperactivity disorder participating in psychopharmacology clinical trials.

IMPORTANCE: There is concern that increased mortality risk among patients with psychiatric illness may be worsened by psychopharmacological agents. OBJECTIVES: To assess mortality risk among adult patients with a diagnosis of schizophrenia, depression, bipolar disorder, anxiety disorders, or attention-deficit/hyperactivity disorder participating in clinical trials conducted by pharmaceutical companies for US Food and Drug Administration (FDA) approval to market and to evaluate if psychopharmacological agents worsen this risk. DATA SOURCES: The FDA Summary Basis of Approval (SBA) reports of new drug applications and supplemental applications for 28 psychopharmacological agents approved between 1990 and 2011. STUDY SELECTION: The FDA SBA reports detailing exposure data from acute placebo-controlled trials and safety extension studies including 92,542 patients from 47 adult drug approval programs for treatment of schizophrenia, depression, bipolar disorder, anxiety disorders, or attention-deficit/hyperactivity disorder and SBA reports on combination and maintenance therapy programs for treatments of bipolar disorder. DATA EXTRACTION AND SYNTHESIS: We reviewed and synthesized mortality data from SBA reports that combined mortality rates across the clinical trials, including information on patient exposure years (PEY) for active treatments and placebo for individual indications. MAIN OUTCOMES AND MEASURES: Overall mortality rate per 100,000 PEY in relation to the psychiatric diagnosis of the patients participating in psychopharmacology clinical trials. Also, the overall mortality rates using PEY technique among patients assigned to psychopharmacological agents or placebo were evaluated. RESULTS: Overall, mortality risk was high and significantly associated with psychiatric diagnosis (χ²4 = 1760; P < .001). Compared with the general adult population, patients with schizophrenia had the highest mortality risk (3.8-fold increase), followed by patients with depression (3.15-fold increase) and bipolar disorder (3.0-fold increase). The mortality risk was not increased when patients were assigned to psychotropic agents rather than placebo except for heterocyclic antidepressants. Suicide accounted for 109 of all 265 deaths (41.1%). CONCLUSIONS AND RELEVANCE: These data suggest that increased mortality rates reported in population studies are detectable among adult patients with psychiatric illnesses participating in psychopharmacological trials. Furthermore, 3- to 4-month exposure to modern psychotropic agents, such as atypical antipsychotic agents, selective serotonin reuptake inhibitors, and selective serotonin-norepinephrine reuptake inhibitors does not worsen this risk. Given the inherent limitations of the FDA SBA reports, further research is needed to support firm conclusions.