Ethics in clinical trial regulation: ethically relevant issues from EMA inspection reports.

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.

Factors Contributing to the Efficacy-Effectiveness Gap in the Case of Orphan Drugs for Metabolic Diseases.

INTRODUCTION: Authorization of orphan medicinal products (OMPs) is often based on studies with several methodological shortcomings. Hence, data are difficult to interpret and efficacy does not always correspond to real-world effectiveness. We investigated to what extent an efficacy-effectiveness gap exists for OMPs for metabolic diseases and set out to explore which factors contribute to it. METHODS: We included all OMPs for rare metabolic diseases authorized in the EU up to 1 January 2016. Efficacy data were obtained from European Public Assessment Reports, relative effectiveness data from the Dutch National Healthcare Institute website, and real-world effectiveness data from literature and interviews with experts and patients. Efficacy and effectiveness were scored as 'no effect', 'unclear' or 'good' based upon a prespecified scoring system. RESULTS: We identified 31 authorized OMPs, of which 21 had post-marketing studies available, thus making it possible to score real-world effectiveness. Eight of 21 (38%) OMPs had a 'good' real-world effectiveness. The use of a clinical or validated surrogate primary endpoint and a representative study population seemed to be related to good effectiveness in the real world, as were type of marketing authorization, study population and disease prevalence. CONCLUSIONS: This study revealed that less than half of the authorized OMPs are effective in the real world. Since the type of primary endpoint used in the pivotal study seems to be associated with good real-world effectiveness, it is important to agree upon study endpoints through early dialogues among relevant stakeholders.

Net gain analysis, an addition to responder analysis--The case of antipsychotic treatment of acute mania.

Net Gain Analysis (NGA) is proposed as an alternative to Responders Analysis (RA) as a more comprehensive method to tap clinical relevance of the effect of treatment. NGA is the group difference in responders minus the group difference in deteriorators; while RA is the group difference in responders. We examined the performance of these two methods in a dataset consisting of individual patient data from 10 randomized controlled trials (N = 2666) of five different antipsychotics in patients with acute mania by comparing the rank ordering of the five compounds according to both systems (NGA and RA). The rank order did not differ between the 2 systems but the inferiority of one compound was revealed more evidently by the NGA in comparison to the RA.

Efficacy of drug treatment for acute mania differs across geographic regions: An individual patient data meta-analysis of placebo-controlled studies.

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.

Placebo response in antipsychotic trials of patients with acute mania: Results of an individual patient data meta-analysis.

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.

The risk-based approach to ATMP development - generally accepted by regulators but infrequently used by companies.

Advanced therapy medicinal products (ATMPs) are the cutting edge of drug innovation. ATMPs have different challenges than other drug classes. To accommodate these challenges and facilitate science-driven development, flexibility in the requirements to demonstrate the safety and efficacy of this rapidly evolving drug class is necessary. To create flexibility, the European Union introduced the risk-based approach. This approach provides the possibility of omitting guideline-based studies based on risk analyses. To gain insight into the effect of the risk-based approach on the non-clinical development of ATMPs, two questions are addressed in this paper. Firstly, "Do companies use a risk-based approach for the non-clinical development of ATMPs?" and, secondly, "Does the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) accept non-clinical development programs based on the risk-based approach?" Scientific advice letters formulated by the CHMP were analyzed. The risk-based approach was used to justify deviations from the guidelines in the majority (75%) of the cases. The CHMP accepted 40% of the proposals to omit studies and stated that additional data was necessary to make an informed decision for 35% of the proposals. This indicates that the risk-based approach facilitates the science-driven development of ATMPs.

EU marketing authorization review of orphan and non-orphan drugs does not differ.

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.

The validity of biomarkers as surrogate endpoints in Alzheimer's disease by means of the Quantitative Surrogate Validation Level of Evidence Scheme (QSVLES).

OBJECTIVE: 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). PROCEDURE: 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. RESULTS: MRI, PET and MRS measures attained a total validity score of 4, NAA/Cre a total score of 5, and cerebral blood flow (SPECT), Abeta , 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). CONCLUSION: 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.

No effects of l-dopa and bromocriptine on psychophysiological parameters of human selective attention.

Patients with schizophrenia exhibit diverse cognitive deficits, one of which is a loss of the ability to focus attention. According to the revised dopamine hypothesis of schizophrenia both an increased mesolimbic and a decreased prefrontal dopaminergic activity is suggested to be involved in schizophrenia. The current study was designed to explore the relationship between dopamine and two psychophysiological parameters of selective attention, i.e. P300 amplitude and processing negativity (PN) in healthy volunteers. In two separate experiments, with a double-blind, balanced and placebo-controlled crossover design, 18 healthy male volunteers were orally administered either 300 mg l-dopa (precursor of dopamine) or placebo (experiment I), or 1.25mg bromocriptine (D2 agonist) or placebo (experiment II). Following this treatment they were tested in an auditory, dichotic selective attention paradigm. An increase in P300 amplitude was found following deviant stimuli when compared to standard stimuli and following attended stimuli when compared to unattended stimuli, regardless of treatment. Similarly, PN was found regardless of treatment. Neither l-dopa nor bromocriptine affected task performance or the amplitudes of PN or P300. In the present study neither l-dopa nor bromocriptine affected PN, P300 amplitude or task performance in healthy controls, phenomena which are usually found to be disrupted in schizophrenia. This indicates that P300 amplitude and PN are neither affected by a global (l-dopa) increased dopaminergic activity, nor by a more selectively towards striatal areas targeted (bromocriptine) increase in dopaminergic activity.

Prevalence of diabetes mellitus in chronic schizophrenic inpatients in relation to long-term antipsychotic treatment.

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.

Increasing dopaminergic activity: effects of L-dopa and bromocriptine on human sensory gating.

Schizophrenic patients show a loss of sensory gating, which is reflected in a reduced P50 suppression. Because most of the symptoms in schizophrenia can be reduced by antagonists of the dopaminergic (D2) system, the loss in sensory gating might be related to an increased dopaminergic activity. Therefore, in the present study, the effects of increased dopaminergic neurotransmisson on sensory gating in healthy volunteers were investigated. In a double-blind, balanced, placebo-controlled design, healthy male volunteers were challenged in two separate studies with either 300 mg L-dopa (precursor of dopamine) or placebo (n=16) and 1.25 mg bromocriptine (D2 agonist) or placebo (n=17). Subsequently, they were tested for their sensory gating (P50 suppression). P50 suppression values in the placebo condition were comparable to those found in literature. Although both L-dopa and bromocriptine reduced P50 amplitude, they did so in an equal ratio for both the response to the conditioning (C) and the testing (T) stimuli, therefore not resulting in a reduction of the P50 suppression ratio (T/C). In the present study, neither L-dopa nor bromocriptine reduced sensory gating in healthy volunteers. This suggests that an increased dopaminergic activity in humans is not responsible for the reduction in sensory gating as seen, for example, in schizophrenia.

[Schizophrenia and diabetes mellitus: not an improbable combination]. / Schizofrenie en diabetes mellitus: geen onwaarschijnlijke combinatie.

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 effect of olanzapine treatment on monoamine metabolite concentrations in the cerebrospinal fluid of schizophrenic patients.

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.

Effect of clozapine on caudate nucleus volume in relation to symptoms of schizophrenia.

OBJECTIVE: Studies have found that caudate volume increased after treatment with typical antipsychotics in patients with schizophrenia but decreased after treatment was changed to clozapine. In the current study the authors examined whether this volume decrease was related to clinical improvement. METHOD: Twenty-eight patients with schizophrenia who had not responded to treatment with typical antipsychotics were included in the study; 22 completed the study. Caudate volume was assessed by using magnetic resonance imaging during treatment with typical antipsychotics and after 24 weeks and 52 weeks of clozapine treatment. Symptoms were assessed just before clozapine treatment and once a month thereafter. RESULTS: Clozapine treatment resulted in a significant reduction in left caudate volume in patients who responded to the drug but not in patients who did not respond to clozapine at 52 weeks of treatment. Overall, the degree of reduction in left caudate volume was significantly related to the extent of improvement in positive and general symptoms but not in negative symptoms. CONCLUSIONS: These findings suggest that the caudate nucleus plays a role in the positive and general symptoms of schizophrenia.

Stress in schizophrenia: an integrative view.

Stress and the development of a (schizophrenic) psychosis are inextricably related. The process by which stress actually affects psychosis is far less clear. The hypothalamic-pituitary-adrenal system, and in particular the release of corticosteroids, has been attributed an essential role. However, schizophrenia is a disorder in which many functions are distorted. Dysfunctions can be found in behavior, cognition, coping, physiology, pituitary-adrenal and immune functioning. In this short paper, these functions are discussed as to how they contribute to the way stress is appraised and processed. Schizophrenic patients are impaired in their biological response to stress by showing a blunted cortisol response to psychosocial stress. It is hypothesized that this reflects rather cognitive dysfunction, based on biological dysfunctions in those brain structures that are responsible for these processes, i.e. the prefrontal cortex and the limbic system. Considering the blunted cortisol response as a maladaptive stress response, its consequences are commented on with an emphasis on the immune system. Finally, the role of neuroleptics, and in particular the atypical ones, is discussed for their beneficial effect, beyond their fear-and anxiety-reducing properties, in restoring some of the cognitive dysfunctions schizophrenic patients display. By doing so, they may improve perception of the environment, enhance adjustment and thus a proper stress response. Integration of these processes in stress research described, may provide new vistas of the stress concept in schizophrenia.

Unresponsiveness to psychosocial stress in a subgroup of autistic-like children, multiple complex developmental disorder.

In this study, we tried to replicate the finding of a diminished cortisol response to stress in autistic-like patients in a more homogenous Multiple Complex Developmental Disorder (MCDD) group. MCDD forms a distinct group within the autistic-like disorders, characterized by impaired regulation of anxiety and affective state, impaired social behavior/sensitivity, and thought disorder. A number of MCDD children develop schizophrenia in adult life. Responses to a psychosocial stressor, consisting of speaking in public while recorded on video, were measured in 10 MCDD children and 12 healthy control children. The public speaking test was imbedded in a two-hour test session, and compared to a control test session. Hypothalamic-pituitary-adrenal (HPA) responses were measured on salivary cortisol at about 20-minute intervals. Heart rate was measured continuously. Delta AUC's were computed for both heart rate (dAUCHR) and salivary cortisol (dAUCCORT), as a measure of response to the test.The public speaking task resulted in significant responses in heart rate and salivary cortisol in healthy control children, but not in MCDD children. dAUCHR was 3.28+/-2.37 in healthy control children, but -0.09+/-1.73 in MCDD children (t=3.31, P<0.01). dAUCCORT was 3.22+/-3.16 in healthy control children, but 0. 17+/-1.74 in MCDD children (t=2.72, P<0.05).The impaired responses to psychosocial stress found in MCDD children may be the result of their limited abilities to react adequately to their (social) environment. The same impairment in stress processing has been found in schizophrenia, and might be a factor in the vulnerability of these MCDD children to develop schizophrenia.

Prenatal exposure to famine and brain morphology in schizophrenia.

OBJECTIVE: The authors assessed the effects of nutritional deficiency during the first trimester of pregnancy on brain morphology in patients with schizophrenia. METHOD: Nine schizophrenic patients and nine healthy comparison subjects exposed during the first trimester of gestation to the Dutch Hunger Winter were evaluated with magnetic resonance brain imaging, as were nine schizophrenic patients and nine healthy subjects who were not prenatally exposed to the famine. RESULTS: Prenatal famine exposure in patients with schizophrenia was associated with decreased intracranial volume. Prenatal Hunger Winter exposure alone was related to an increase in brain abnormalities, predominantly white matter hyperintensities. CONCLUSIONS: Nutritional deficiency during the first trimester of gestation resulted in an increase in clinical brain abnormalities and was associated with aberrant early brain development in patients with schizophrenia. Stunted brain development secondary to factors that affect brain growth during the first trimester of gestation may thus be a potential risk factor for developing schizophrenia.