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Background: Within the EU, regulators are obliged to take ethical issues into consideration during marketing authorization deliberation. The goal of this manuscript is to identify what kinds of ethical issues regulators encounter during marketing authorization application deliberations, and the incidence of these ethical issues.Methods: This study used an EMA-provided Excel file that contains all the GCP non-compliance findings from all inspection reports from 2008-2012. There were 112 medicinal products and a total of 288 clinical trial sites. There were a total of 4014 GCP non-compliance findings. The findings that were ethically relevant were extracted using NVivo 10.0 and categories for the ethically relevant findings (ERFs) were created. Note was taken of the incidence of ERFs for each category and the inspectors' gradings of these findings were extracted. This study also looked at the mean and the maximum number of ERFs per grading per medicinal product application, as well as the number of medicinal products with at least one ERF and those with at least major ERFs.Results: With multiple coding, there were 1685 ERFs. ERFs were present in almost all of the medicinal products (97.3%). The majority of ERFs were graded as major. At least major ERFs were present in almost all medicinal products with ERFs. The categories with the highest number of ERFs were protocol issues, patient safety, and professionalism issues. In terms of the density of combined critical and major findings, monitoring and oversight, protocol issues, and respect for persons top the list. This study also showed that, on average, there were 7.54 major and 2.95 critical ERFs per medicinal product application, although ERFs can increase to 30 major and 12 critical.Conclusion: Regulators regularly encounter ERFs that at least "might adversely affect the rights, safety or well-being of the subjects". It remains to be explored how regulators respond to these ethical issues. [ABSTRACT FROM AUTHOR]

Given globalization trends in the conduct of clinical trials, the external validity of trial results across geographic regions is questioned. The objective of this study was to examine the efficacy of treatment in acute mania in bipolar disorder across regions and to explain potential differences by differences in patient characteristics. We performed a meta-analysis of individual patient data from 12 registration studies for the indication acute manic episode of bipolar disorder. Patients (n = 3207) were classified into one of three geographic regions: Europe (n = 981), USA (n = 1270), and other regions (n = 956). Primary outcome measures were mean symptom change score on the Young Mania Rating Scale (YMRS) from baseline to endpoint and responder status (50% improvement form baseline). Effect sizes were significantly smaller in the USA (g = 0.203, 95% confidence interval (CI) 0.062–0.344; odds ratio (OR) 1.406, 95% CI 0.998–1.980) than in Europe (g = 0.476, 95% CI 0.200–0.672; OR 2.380, 95% CI 1.682–3.368) or other regions (g = 0.533, 95% CI 0.399–0.667; OR 2.300, 95% CI 1.800–2.941). Regional differences in age, gender, initial severity, body mass index, placebo response, discontinuation rate, and type of compound could not explain the geographic differences in effect. Less severe symptoms at baseline in the US patients did explain some of the difference in responder status between patients in Europe and the USA. These findings suggest that the results of studies involving patients with acute mania cannot be extrapolated across geographic regions. Similar findings have been identified in schizophrenia, contraceptive, and in cardiovascular trials. Therefore, this finding may indicate a more general problem regarding the generalizability of pharmacological trials over geographic regions. [ABSTRACT FROM AUTHOR]

Background: There is little information on the status of the implementation of the isotretinoin Pregnancy Prevention Programme (PPP) in the EU, and on compliance with this programme by the regulatory agencies.Objective: The aim of the study was to obtain information on implementation of the harmonized PPP of isotretinoin in the EU member states plus Norway and Iceland.Materials and Methods: In January 2009, a questionnaire (request for non-urgent information [NUI]) was sent to all 25 EU member states, plus Norway and Iceland, to collect information on the implementation status of the PPP and its effectiveness.Results: The response rate was 82% (22 of the 27 countries). In 21 of the 27 member states, isotretinoin is marketed and the PPP is in force, and in 18 of the 22 responding countries, the total required elements (seven) following a formal EU review are incorporated in the PPP. Seven member states had additional measures in place. In spite of implementation of the PPP and additional measures, a total of 143 isotretinoin-exposed pregnancies have been reported in 16 of the 22 responding member states since implementation of the harmonized PPP.Conclusions: Despite implementation of the isotretinoin PPP in most member states, isotretinoin-exposed pregnancies were reported. This has led some member states to implement additional measures to the PPP, resulting in inconsistency with the approach agreed in 2003 following the European-wide review. It has been further suggested that common elements should be developed for PPPs for all medicines that are known to carry a high teratogenic risk. [ABSTRACT FROM AUTHOR]

To evaluate the validity of biomarkers that are currently being proposed as potential surrogate endpoints in AD clinical trials with the aid of the “Quantitative Surrogate Validation Level of Evidence Schema” (QSVLES) proposed by Lassere et.al. (1). A Pubmed literature search was conducted to identify AD biomarkers with SEP potential, and the QSVLES was applied to determine the extent of the SEP validity. MRI, PET and MRS measures attained a total validity score of 4, NAA/Cre a total score of 5, and cerebral blood flow (SPECT), A, Tau and APP a total score of 2. None of these biomarkers could fall into the rank of Levels 1 or 2, reserved for SEPs, according to the QSVLES criteria. This was mainly attributed to the lack of sufficient evidence that was derived from high ranking studies (RCT, prospective observational studies). Though residing on SEPs as sole determinants of the benefit/risk ratio of AD medications seems to be pretty far, there could be certain cases where the use of SEPs may be beneficial, making efficient therapies available faster when there is a major public health interest involved. However, the potential risks of relying on invalid SEPs should not be underestimated and therefore the research on SEP validation and the development of specific validation guidance should be encouraged. The QSVLES, though not devoid of criticism, may be proposed as a starting point. [ABSTRACT FROM AUTHOR]

In the development process for new drugs, dose-finding studies are of major importance. Absence of these studies may lead to failed phase 3 trials and delayed marketing authorization. In our study we investigated to what extent dose-finding studies are performed in the case of orphan drugs for metabolic and oncologic indications. We identified all orphan drugs that were authorized until August 1, 2017. European Public Assessment Reports were used to extract the final dose used in the summary of product characteristics, involvement of healthy volunteers, study type, end points used, number of patients, number of doses, studies in special populations, and dose used for phase 3 studies. Each drug was checked for major objections and dose changes postmarketing. We included 49 orphan drugs, of which 28 were indicated for metabolic disorders and 21 for oncologic indications. Dose-finding studies were performed in 32 orphan drugs, and studies in healthy volunteers in 26. The absence of dose-finding studies was mostly due to the rarity of the disease. In this case the dose was determined based on factors such as animal studies or clinical experience. Dose-related major objections were raised for 9 orphan drugs. Postmarketing dose-finding studies were conducted in 18 orphan drugs, but dose changes were applied in only 2 drugs. In conclusion, dose-finding studies in the case of metabolic and oncologic orphan drugs were conducted in the development programs of two thirds of orphan drugs. Dose-finding studies performed postmarketing suggest that registered doses are not always optimal. It is thus important to perform more robust dose-finding studies both pre- and postmarketing., (© 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Marketing authorisation application dossiers relating to medicinal products containing new active substances and evaluated by the European Medicines Agency (EMA) over the period 2012-2015 were examined. Major objections and other concerns relating to efficacy and safety of the day 80 assessment reports were reviewed. Overall, approved products have more subgroup concerns than nonapproved products, which seems to be a consistent pattern. Subgroup analyses are mainly assessed to have the insurance that subgroups of patients that might lack a positive benefit: risk ratio will not be wrongly included in the approved treatment indication., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Inexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Reimbursement is at the discretion of health insurance companies, and may be unpredictable. The example addressed was ephedrine as add-on treatment for myasthenia gravis. Stakeholders from academia, a patient organization, the Dutch National Health Care Institute (NHCI) and Dutch Medicines Evaluation Board (MEB) advised on the trial design. The NHCI and MEB agreed to provide scientific advice on the suitability of the evidence generated by the trial, for regulatory decisions. This paper describes the feasibility of the trial and the utility of its aggregated results., Results: The trialists experienced the trial as feasible. Retrospective interviews showed that the trial as performed was acceptable to patients. The treatment effect in the primary outcome measure, muscle strength, was statistically significant when inferred to the population level, though the effect size was modest. Secondary outcomes were statistically significant in a preplanned, fixed effects analysis within the four patients. The NHCI advised that it could potentially make reimbursement decisions based on the Fitting Evidence framework, should the trialists decide to apply for reimbursement. The MEB advised that for a licensing decision, the N-of-1 design is a last-resort option for demonstrating treatment benefit in a rare disease. N-of-1 trials alone do not provide enough evidence on potential risk. The MEB found the current trial inconclusive. It suggested doing a 2-armed trial of longer duration, possibly with a different outcome measure (postponement of corticosteroid use). It suggested engaging a consultancy or commercial sponsor, should the trialists decide to seek market authorization of the drug., Conclusions: In theory, evidence from aggregated N-of-1 trials is suitable for use in licensing and reimbursement decisions. The current example illustrates differences in interpretation of N-of-1 results by health authorities. In the era of personalized medicine, consensus is required on the interpretation of data from study designs geared to small groups. Demonstrating effectiveness of inexpensive medicines in small populations may require involvement of non-commercial parties, to preserve affordability.

Our objectives are to describe the procedure for qualification advice and opinion from EU regulators on the use of novel methodologies in drug development, the key stakeholders involved and the evidence requirements for qualification opinion. We present a case study of the request from the Coalition Against Major Disease (CAMD) Consortium of the Critical Path (C-Path) Institute for EU regulators׳ qualification opinion on the use of low hippocampal volume as a biomarker for population enrichment in clinical trials of novel drugs in Alzheimer׳s disease (AD). We discuss the main concerns from the regulators, data analysis requests and guidance during the qualification. EU regulators concluded that low hippocampal volume, measured by vMRI and considered as a dichotomized variable (low volume or not), appears to help enriching recruitment into clinical trials aimed at studying drugs that potentially slow the progression of the pre-dementia stage of AD. The biomarker qualification procedure is a dynamic process in which pharmaceutical companies and research consortia can submit further data to update the qualifications and improve the predictive value of the biomarkers., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

We examined the role of placebo response in acute mania trials. Specifically, whether placebo response: (1) predicts treatment effect, (2) can be predicted by patient and study characteristics, and (3) can be predicted by a parsimonious model. We performed a meta-analysis of individual patient data from 10 registration studies (n=1019) for the indication acute manic episode of bipolar disorder. We assessed the effect of 14 determinants on placebo response. Primary outcome measures were mean symptom change score (MCS) on the Young Mania Rating Scale (YMRS) and response rate (RR), defined as ≥ 50% YMRS symptom improvement from baseline to endpoint. The overall placebo response was 8.5 points improvement on the YMRS (=27.9%) with a RR of 32.8%. Placebo response was significantly associated with the overall treatment response. Five determinants significantly (p<0.05) predicted the placebo response. The multivariate prediction model, which consisted of baseline severity, psychotic features at baseline, number of geographic regions, and region, explained 10.4% and 5.5% of the variance in MSC and RR, respectively. Our findings showed that the placebo response in efficacy trials of antipsychotics for acute mania is substantial and an important determinant of treatment effect. Placebo response is influenced by patient characteristics (illness severity and presence of psychotic features) and by study characteristics (study year, number of geographic regions and region). However, the prediction model could only explain the placebo response to a limited extent. Therefore, limiting trials to certain patients in certain geographic regions seems not a viable strategy to improve assay sensitivity., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Marketing authorization application dossiers of 17 orphan drugs (ODs) and 51 non-ODs evaluated by the European Medicines Agency (EMA) in the period 2009-2010 were compared. We aimed to identify whether any differences existed between ODs and non-ODs in number and type of deficits brought forward during the EMA review, regarding the clinical development plan, clinical outcome and medical need and studied whether these deficits were similarly associated with marketing approval in the EU. In 71% of the ODs dossiers and 65% of the non-ODs dossiers marketing approval was granted. Differences in deficits were found, but similarities in the way ODs and non-ODs were reviewed and marketing approval decisions were taken, underline that regulatory standards are equally high., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The use of placebo in clinical trials, and, related to this, ethical and feasibility aspects, are often debated. However, regulatory authorities must ensure that only new drugs with a positive benefit/risk would be granted a marketing authorization. It is therefore not surprising that they often put forward the need for placebo control in clinical trials in an area where many trials fail, and assay sensitivity is not self-evident. To illustrate the complexity that regulatory authorities encounter when faced with the registration dossier of products in the main psychiatric therapeutic areas, Major Depressive Disorder (MDD) and schizophrenia, the trial outcome for products receiving an opinion in the EU during the past 15 years were reviewed., Data Source: European Public Assessment Reports and registration files., Results: A total of 45 studies qualified for analysis. For the indication MDD 38% of the studies (10/26) were recorded as failed, and another 15% (4/26) as negative. For schizophrenia, these figures were 16% (3/19) and 11% (2/19). Further exploration of the trials in MDD revealed an inconsistent pattern in terms of magnitude of placebo- and drug-mediated response (i.e. similar studies with consistent placebo response provided different treatment outcomes)., Conclusion: From a regulatory perspective the dilemma of a priori exclusion of the placebo arm in clinical trials in the domains of depression or schizophrenia cannot be solved at this time as long as factors influencing trial variability are not better identified or understood. This counts in particular for MDD where the added drug effect is not consistent across trials with almost identical inclusion criteria. Unfortunately, this trend has not changed over the past 15 years. However, all efforts should be taken to optimize the clinical development of drugs in the psychiatric domain, and improve the intrinsic quality of the clinical trials in order to allow for a different viewpoint., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

Child and adolescent psychiatry is a relatively young field and the recognition, classification, and treatment of disorders in children and adolescents lag behind those in adults. In recent years there is an increasing awareness of the differences between children and adults in psychopathology and pharmacology. Related to this new paediatric regulations have been introduced. This article reviews the regulatory and legislative measures that were adopted in the EU in 2007 and the subsequent impact of these measures on the field of paediatric psychopharmacology. The consequences of the paediatric regulation in the EU are reflected in several domains: regulatory, research aimed at drug development and clinical practices. In the regulatory domain, the consequences include: new paediatric indications, inclusion of special (class) warnings, specification of dose regimens, and information on safety specific to children and adolescents, and development of new medicinal formulations. The paediatric regulation leads to timely development of paediatric friendly formulations and better quality of the clinical evidence. In clinical practices, an increased awareness of the uniqueness of paediatric pharmacology is emerging among medical professionals, and subsequent improvement of medical care (i.e. correct doses, appropriate formulation, monitoring for expected adverse events). In addition, clinical guidelines will have to be revised more frequently in order to integrate the recently acquired knowledge. The new regulations stimulate transparency and discussions between academia, pharmaceutical industry, and regulators. The purpose is to optimize clinical research and obtain evidence for paediatric psychopharmacology, thereby providing adequate support for treatment., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Selective publication can have a deleterious effect on evidence based medicine, health policy decision making and treatment guidelines. Using the European Public Assessment Reports (EPARs) as reference, this study examined selective publication and selective reporting of efficacy and safety of insomnia medication. EPARs of with three insomnia medications were used to identify all clinical trials that were performed between 1998 and 2007 for the purpose of registration in the EU. The matching publication for each trial was searched through a systematic literature search. Accuracy of information in the publications was examined by comparison to the information in the EPARs. Only 55% of the trials with insomnia medications identified in EPARs were published. Positive trials were approximately two times more likely to be published. The lag time from study completion to publication was shorter for the positive compared to the negative trials. Sample size did not correlate with publication of negative trials. The meta-analysis of the effect size of insomnia medication was 1.6 times larger in the published data compared to the complete data. While the primary end points of the trials were reported reliably in the publications, remarkable inconsistencies were detected in the reporting of the secondary end points, methods, results and, especially safety. In conclusion, selective publication and reporting lead to an overestimation of efficacy and underestimation of safety of insomnia products. Authors of treatment guidelines should be aware of this bias. EPARs/FDA reviews provide a more unbiased view of the benefit-risk balance of insomnia and other medications and hence these documents should be consulted by e.g. authors of meta-analyses and of treatment guidelines., (Copyright © 2010 Elsevier B.V. All rights reserved.)

In this essay, we focus on empathy in children and adolescents with disruptive behavior disorders (DBD), based on the assumption that lack of empathy is a risk factor for the development of DBD. We reflect on the heterogeneity of DBD, the complex nature of the empathy construct, discuss empathy's role in aggression, and review recent findings from studies on empathic skills in children and adolescents with DBD. Research suggests that the mechanisms underlying empathy problems may be different for DBD subtypes. Individuals with psychopathic tendencies may show a selective impairment in empathy with sadness and fear due to abnormalities in neural circuits connected with the amygdala. Individuals without these tendencies may show little empathy for a variety of reasons, such as hostile attributions, anxiety and/or poor regulatory skills. Understanding more about the nature and causes of empathy dysfunction in DBD could aid in identifying subtypes and help to improve prevention and intervention programs. Suggestions for future research are made.

Pharmacological treatment of children and adolescents is largely based on evidence from adults' studies. There is, however, growing awareness that this evidence cannot simply be extrapolated to children. The Dutch Medicines Evaluation Board (MEB) in collaboration with the Child and Adolescent section of the Dutch Association of Psychiatry and the National Expertise Centre Child and Adolescent Psychiatry have organised a workshop to discuss the kind of evidence that would be necessary and the methods involved. There was consensus about the need to demonstrate efficacy in targeted disorders as well as symptoms within specific disorders and about the need for separate evidence for children and for adolescents. In addition, too little is known about safety, especially long-term safety, as consequences of treatment. Main issues are effects on growth, cognitive, motor, emotional, and sexual development, metabolic symptoms, cardiotoxicity, and dependence. Specific methodological issues were discussed, such as the role of different informants and the high rate of comorbidity.

In a previous study, we found an association between 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C) polymorphisms and the occurrence of the metabolic syndrome in patients using antipsychotics. In the current study, we set out to replicate our findings in another sample of patients and to explore in a pooled analysis of both samples the influence of the effect of individual antipsychotics. Data for this cross-sectional study came from 2 different samples, the original sample (n = 112) and the replication sample (n = 164). Primary end point was the prevalence of the metabolic syndrome as classified by a modified version of the National Cholesterol Education Program's Adult Treatment Panel III. Primary determinants were polymorphisms in the promoter region of the HTR2C gene [HTR2C:c.1-142948(GT)n, rs3813929 (-759 C/T), and rs518147 (-697 G/C)] and an intragenic polymorphism (rs1414334:C>G). The variants of HTR2C:c.1-142948(GT)n (odds ratio [OR], 1.69; 95% confidence interval [CI], 0.75-3.81) and rs1414334 (OR, 2.35; 95% CI, 0.96-5.77) were not significantly associated with the metabolic syndrome in the replication sample but did show significance in the pooled analysis (OR, 2.09; 95% CI, 1.12-3.91; and OR, 2.35; 95% CI, 1.19-4.62, respectively). The variant rs1414334 C allele was specifically associated with the metabolic syndrome in patients using clozapine (OR, 9.20; 95% CI, 1.95-43.45) or risperidone (OR, 5.35; 95% CI, 1.26-22.83). This study extends previous findings to a larger sample of patients and implicates specific antipsychotic drugs. The increased risk for the metabolic syndrome is particularly strong in carriers of the rs1414334 C allele using clozapine or risperidone.

Background: Many reports indicate that the incidence and prevalence of diabetes mellitus is increased in schizophrenic patients and related to antipsychotic treatment. In an exploratory cross-sectional study we assessed the prevalence of type 2 diabetes mellitus in 266 chronic schizophrenic and schizoaffective inpatients and investigated whether the duration of antipsychotic treatment was related to the development of diabetes mellitus., Method: We measured the non-fasting plasma glucose level in 266 inpatients with DSM IV diagnosis of schizophrenia or schizoaffective disorder in 5 different long-stay wards in the Netherlands. Measured variables were: age, sex, ethnicity, BMI, current antipsychotic treatment, duration of illness and duration of antipsychotic treatment., Results: The overall prevalence of type 2 diabetes mellitus was 9%, which is significantly higher than the prevalence of 4.9% in the general population (OR 1.89, CI 1.14-3.13; p<0.014). The prevalence was increased in two age cohorts: 30-39 years (3.8% vs. 0.3%, OR=13.29, CI=2.17-81.36, p=<0.005) and 40-49 years (9.3% vs. 1.5%, OR=6.74, CI=2.77-16.38, p=0.000). No new cases of diabetes mellitus were detected during the course of the study. The increased prevalence was found to be related to overweight and obesity. The time of exposure to antipsychotic treatment was not significantly correlated with the prevalence of diabetes mellitus when adjusted for age (F=0.804, df=1, p=0.371, respectively, F=0.194, df=1, p=0.660). Both typical and atypical antipsychotics contributed equally to the prevalence of diabetes mellitus., Conclusion: No significant relation between long-term antipsychotic treatment and prevalence of diabetes mellitus was found. The high prevalence of diabetes mellitus in schizophrenic patients warrants screening of these patients already at young age for glucose disturbance.

Three male schizophrenia patients, aged 41, 40 and 61 years respectively, who had undergone treatment without a satisfactory result, were treated with the antipsychotic clozapine. Diabetes mellitus developed within a period of several months to several years. The antipsychotic medication could be continued once the patients had been started on blood-glucose lowering medication. There seems to be an increased incidence of type-2 diabetes mellitus in patients with schizophrenia. It has been suggested that treatment with neuroleptics, especially atypical neuroleptics, provokes the onset of diabetes mellitus. The relatively young age (often < 50 years) at onset is a cause for concern. From a pathophysiological viewpoint, an increased prevalence of diabetic risk factors has been suggested for schizophrenia in addition to the toxic effect of neuroleptics in general. The possible consequences for the general health of this vulnerable group of patients warrant recommendations concerning the regular monitoring of these patients during treatment.

The mechanism of action of both typical antipsychotics and the atypical antipsychotic, clozapine, may be related to the (changing) interaction of dopamine and serotonin in schizophrenia. This study examined the effect of olanzapine in schizophrenic patients on cerebrospinal fluid (CSF) metabolites of dopamine (homovanillic acid, HVA) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA). Twenty-three male schizophrenic patients, who were drug-free for at least 2 weeks (mean drug-free period of 35 days +/- 43; median 16 days), underwent a lumbar puncture (LP). Patients were subsequently treated with olanzapine 10 mg/day for 6 weeks, after which the LP was repeated. CSF was assayed for HVA and 5-HIAA concentrations. Psychiatric symptoms were rated once a week. Olanzapine significantly increased HVA concentrations and the HVA/5-HIAA ratio while 5-HIAA concentrations were not altered. These changes did not significantly correlate with treatment response. A negative correlation was found between HVA concentrations and negative symptoms after olanzapine treatment. In conclusion, olanzapine treatment increases HVA concentrations and the HVA/5-HIAA ratio in CSF of schizophrenic patients, but these changes are unrelated to its clinical efficacy.