Future of the drug label:Perspectives from a multistakeholder dialogue

'Regulating drugs does not end when market access has been granted. Monitoring drugs over the life-cycle has become state of the art, inherent to evolving legislation and societal need. Here, we explore how the drug label could move along in a changing playing-field, and become a sustainable label for the future. A dialogue between academia, government, the pharmaceutical industry, and patient/societal organizations was organized by the Regulatory Science Network Netherlands, RSNN. This is their view.

Alignment of European Regulatory and Health Technology Assessments: A Review of Licensed Products for Alzheimer's Disease

Aims: To facilitate regulatory learning, we evaluated similarities and differences in evidence requirements between regulatory and health technology assessment (HTA) bodies of Alzheimer's disease (AD) approved products.Methods: The European marketing authorisation application dossiers and European public assessment reports (EPARs) of the licensed AD drugs were screened to identify the phase III randomised controlled trials (RCTs) and outcomes used. We also screened the assessment reports of the National Institute of Health and Care Excellence (NICE, England) and the National Health Care Institute (ZiN, the Netherlands) to identify the studies and outcomes used in HTA assessments.Results: The application dossiers of donepezil, galantamine, rivastigmine, and memantine contained 16 phase III RCTs in total. These trials were also included in HTA assessments except that NICE excluded studies that were not published (n = 2) or trials that included patients with other types of dementia (n = 3). In the regulatory assessments the focus was on cognitive and global outcomes, and to some extent on function. In the HTA assessments of clinical effectiveness other domains were also covered including: function, behaviour and mood, and, occasionally, quality of life. In the economic analyses of NICE the domains cognition, function, and quality of life were included.Conclusion: There was a large overlap in inclusion of trials in regulatory and HTA assessments, although the focus on specific outcomes slightly differed. Understanding the methods and perceptions of both authorities can stimulate regulatory and HTA cross-talk and further alignment, and therefore more rapid patient access to new treatments

Sex Proportionality in Pre-clinical and Clinical Trials: An Evaluation of 22 Marketing Authorization Application Dossiers Submitted to the European Medicines Agency

This study assessed to what extent women were included in all phases of drug development; whether the clinical studies in the marketing authorization application dossiers include information per sex; and explored whether there are differences between women and men in the drugs' efficacy and safety. Data were extracted from dossiers submitted to the European Medicines Agency. Twenty-two dossiers of drugs approved between 2011 and 2015 for the treatment of various diseases were included. Female animals were included in only 9% of the pharmacodynamics studies, but female and male animals were included in all toxicology studies. Although fewer women than men were included in the clinical studies used to evaluate pharmacokinetics (PK) (29 to 40% women), all dossiers contained sex-specific PK parameter estimations. In the phase III trials, inclusion of women was proportional to disease prevalence for depression, epilepsy, thrombosis, and diabetes [participation to prevalence ratio (PPR) range: 0.91–1.04], but women were considered underrepresented for schizophrenia, hepatitis C, hypercholesterolemia, HIV, and heart failure (PPR range: 0.49-0.74). All dossiers contained sex-specific subgroup analyses of efficacy and safety. There seemed to be higher efficacy for women in one dossier and a trend toward lower efficacy in another dossier. More women had adverse events in both treatment (73.0 vs. 70.6%, p < 0.001) and placebo groups (69.5 vs. 65.5%, p < 0.001). In conclusion, women were included throughout all phases of clinical drug research, and sex-specific information was available in the evaluated dossiers. The included number of women was, however, not always proportional to disease prevalence rates

Drug Shortages From the Perspectives of Authorities and Pharmacy Practice in the Netherlands: An Observational Study

Background: Drug shortages are a potential threat to public health. Reliable data on drug shortages is limited. The objective was to examine the extent and nature of potential drug shortages signaled by authorities and pharmacy practice in the NetherlandsMaterials and Methods: The primary working systems of Dutch authorities (Medicines Evaluation Board and Health and Youth Care Inspectorate) and the archives of pharmacy practice (Royal Dutch Pharmacists Association) from 2012 to 2015 were searched for number, characteristics, overlap, and date of signals on potential drug shortages. Also, the product characteristics of the potential drug shortages were analyzed from the two different sourcesResults: Authorities detected 2.6 times more signals on potential shortages than pharmacy practice. Only 438 (8%) out of 5,731 potential drug shortages were detected by both authorities and pharmacy practice. Signals were detected later by authorities than by pharmacy practice, especially on potential permanent shortages (median difference −180 days (IQR: −4 to −405 days)). Authorities detected by majority (72%) signals related to permanent shortages with relative overrepresentation of rectal products and anti-infectives for systemic use. In contrast, pharmacy practice detected by majority (71%) signals related to temporary shortages with relative overrepresentation of ocular and cutaneous products, anti-infectives for systemic use, products for sensory organs and dermatologicals.Conclusions: Authorities and pharmacy practice detected different signals on potential drug shortages with little overlap. Combining data from both authorities and pharmacy practice seems to be necessary in order to gain a more complete overview and maximum insight in potential drug shortages at a national level. Moreover, the finding that authorities were informed later than pharmacy practice causes concerns in terms of opportunities for authorities to assist pharmacy practice to find solutions for shortages

Requirements for generic anti-epileptic medicines: a regulatory perspective

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The stress-vulnerability hypothesis in psychotic disorders: focus on the stress response systems.

The vulnerabilty stress model is an intriguing concept to look into the etiology of psychotic disorders and, in particular, into the "nature nurture" principle. That stress affects a vulnerable nature may be obvious, but its mechanism is not well understood, and many questions remain to be answered, let alone how to define "vulnerability". The present review tries to focus on the core issues of the vulnerability stress concept--identifying vulnerability, the way stress interferes with it, and the possiblilities of modulating their interaction. Attention is drawn to the biologic stress response systems, the autonomic nervous system (ANS), the hypothalamic pituitary adrenal (HPA) system, and the immune system, and highlights the plasticity of the HPA system as the mediator of adaptation

Selective impairments in the stress response in schizophrenic patients

Objective: In the vulnerability-stress concept of schizophrenia, schizophrenic patients are thought to display increased sensitivity to stress. Little is known about the biological mechanisms that are involved in stress processing in schizophrenic patients. In this study, hypothalamic- pituitary-adrenal (HPA) function in schizophrenic patients was studied for its essential role in stress processing and adaptation to the environment. Methods: Eighteen schizophrenic patients were compared to 21 healthy controls in their salivary cortisol response to a physical (bicycle ergometry) and a psychosocial (public speaking) stressor. Coping questionnaires were included as a measure of stress processing at the psychological level. Basal HPA function was assessed by measuring cortisol day profiles and feedback activity by using dexamethasone and hydrocortisone. Results: Schizophrenic patients showed blunted cortisol responses to the psychosocial stressor, but not to the physical stressor, in spite of similar increases in heart rate. The cortisol response to the psychosocial stressor tended to be negatively correlated to the use of passive and avoidant coping strategies. Basal HPA function appeared intact in the schizophrenic patients. Conclusions: The findings show a selective impairment in the response to psychosocial stress in schizophrenic patients. This suggests the involvement of brain systems that play a role in the activation of the HPA system to psychosocial stress, like arginin-vasopressin (AVP), and cognitive processes, like coping

Pituitary-adrenal function in adolescent psychiatric patients: Impact of depressive symptoms

Background: The aim of this study was to determine whether depressive symptoms affect pituitary-adrenal function in adolescents, as they do in adults. Methods: Salivary cortisol was measured before and after physical exercise in 23 hospitalized adolescent psychiatric patients and 13 age- and sex-matched healthy controls in a placebo-controlled design. In patients, cortisol profiles were assessed from 08:00 to 20:00 h before and after administration of low doses of dexamethasone or the natural steroid hydrocortisone. Patients were classified according to DSM III-R criteria and assigned to either a depressed group (n = 10) or a non-depressed group (n = 13). Subjective depressive symptoms were rated with the 90-item symptom checklist. Results: Physical exercise increased cortisol output significantly in all subjects, but there were no differences between groups. In patients, no differences in basal cortisol levels were found between the depressed and non-depressed groups. Dexamethasone, but not hydrocortisone, was able to suppress cortisol levels in both groups. Differences between groups were only found in total cortisol output over the 3 days when data were analyzed according to the patients 'subjective' feelings of depression, with the highest cortisol levels in the 'subjectively more depressed' patients. Conclusions: The results obtained only partially support the hypothesis that depressive symptoms in adolescent psychiatric patients determine pituitary- adrenal (mal)function, and appear to depend on the strategy used. (C) 2000 Elsevier Science B.V