Methods for Neuroscience Drug Development: Guidance on Standardization of the Process for Defining Clinical Outcome Strategies in Clinical Trials.

Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcomes selection in early clinical trials is key to maximizing the likelihood of identifying new treatments in psychiatry and neurology. The field lacks good standards for designing outcome strategies, therefore The Outcomes Research Group was formed to develop and promote good practices in outcome selection. This article describes the first published guidance on the standardization of the process for clinical outcomes in neuroscience. A minimal step process is defined starting as early as possible, covering key activities for evidence generation in support of content validity, patient-centricity, validity requirements and considerations for regulatory acceptance. Feedback from expert members is provided, regarding the risks of shortening the process and examples supporting the recommended process are summarized. This methodology is now available to researchers in industry, academia or clinics aiming to implement consensus-based standard practices for clinical outcome selection, contributing to maximizing the efficiency of clinical research.

The new European Medicines Agency guideline on antidepressants: a guide for researchers and drug developers.

According to the World Health Organization (WHO), depressive disorders are currently considered as one of the most disabling medical conditions in the world with one of the highest disability-adjusted life years [1] and this situation has apparently been further worsened during the COVID-19 pandemic [2]. Up to two thirds of patients with major depressive disorders (MDD) do not achieve full remission following an adequate first line standard of care and/or experience residual symptoms such as anxiety, impaired cognition, fatigue, sleep disturbance, or anhedonia [3]. Several attempts are often needed to find the most suitable treatment [4]. Thus, there is a need for medicinal products with better efficacy (e.g., faster onset of action, higher rates of response and remission), improved safety and/or more personalised profiles [5].

Nonclinical data supporting orphan medicinal product designations: lessons from rare neurological conditions.

Here, we provide an in-depth literature and experience-based review of nonclinical models and data used to support orphan medicinal product designations (OMPDs) in rare neurodegenerative conditions. The Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency updates its assessment processes based on scientific progress and aims to provide transparent criteria required in support of OMPDs. Thus, we also provide an updated analysis of existing nonclinical models in selected conditions and identify key features of nonclinical studies that are crucial for the support of OMPDs. This could not only inform future drug development in rare neurological conditions, but also indicate areas where the use of nonclinical models can be made more efficient.

Development of Exon Skipping Therapies for Duchenne Muscular Dystrophy: A Critical Review and a Perspective on the Outstanding Issues.

Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping is a therapeutic approach that aims to induce production of partially functional dystrophins. Recently, an AON targeting exon 51 became the first of its class to be approved by the United States regulators [Food and Drug Administration (FDA)] for the treatment of DMD. A unique aspect of the exon-skipping approach for DMD is that, depending on the size and location of the mutation, different exons need to be skipped. This challenge raises a number of questions regarding the development and regulatory approval of those individual compounds. In this study, we present a perspective on those questions, following a European stakeholder meeting involving academics, regulators, and representatives from industry and patient organizations, and in the light of the most recent scientific and regulatory experience.

Stakeholder cooperation to overcome challenges in orphan medicine development: the example of Duchenne muscular dystrophy.

Duchenne muscular dystrophy is a rare, progressive, muscle-wasting disease leading to severe disability and premature death. Treatment is currently symptomatic, but several experimental therapies are in development. Implemented care standards, validated outcome measures correlating with clinical benefit, and comprehensive information about the natural history of the disease are essential for regulatory approval of any treatment. However, for Duchenne muscular dystrophy and other rare diseases, these requirements are not always in place when potential therapies enter the clinical trial phase. A cooperative effort of stakeholders in Duchenne muscular dystrophy-including representatives from patients' groups, academia, industry, and regulatory agencies-is aimed at addressing this shortfall by identifying strategies to overcome challenges, developing the tools needed, and collecting relevant data. An open and constructive dialogue among European stakeholders has positively affected development of treatments for Duchenne muscular dystrophy; this approach could serve as a paradigm for development of treatments for rare diseases in general.

Translational and regulatory challenges for exon skipping therapies.

Several translational challenges are currently impeding the therapeutic development of antisense-mediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and interpretation of appropriate clinical outcome measures. Others are inherent to the antisense oligonucleotide (AON)-mediated exon skipping approach, which employs small modified DNA or RNA molecules to manipulate the splicing process. This is a new approach and only limited information is available on long-term safety and toxicity for most AON chemistries. Furthermore, AONs often act in a mutation-specific manner, in which case multiple AONs have to be developed for a single disease. A workshop focusing on preclinical development, trial design, outcome measures, and different forms of marketing authorization was organized by the regulatory models and biochemical outcome measures working groups of Cooperation of Science and Technology Action: "Networking towards clinical application of antisense-mediated exon skipping for rare diseases." The workshop included participants from patient organizations, academia, and members of staff from the European Medicine Agency and Medicine Evaluation Board (the Netherlands). This statement article contains the key outcomes of this meeting.

Addressing the regulatory and scientific challenges in multiple sclerosis--a statement from the EU regulators.

Improving and facilitating the process of making new drugs available to patients with multiple sclerosis (MS) requires cooperation among the regulators and other stakeholders. This cooperation will also positively contribute towards developing guidelines of the highest quality in medical, regulatory and scientific aspects. This would be beneficial both in areas that require further guideline development, but also in fields where existing guidance should be adapted to take into account evolution in science. Considering the input from all stakeholders, the European Medicines Agency confirmed its intention to update the relevant guideline and apply a flexible approach towards new drug development strategies in MS. This article is the first official position from the EU regulators, presenting the main changes to be expected in the guidance document.

Evaluation of the factors affecting the quality of life and total costs in epilepsy patients on monotherapy with carbamazepine and valproate.

OBJECTIVES: To evaluate the effect of different demographic and clinical factors on the quality of life and cost of treatment of epilepsy patients on monotherapy with carbamazepine and valproate. PATIENTS AND METHODS: A total of 146 patients (67 male, 79 female, age range 18-80 years) with focal and generalized seizures were studied for one year. The patients were allocated into two groups depending on the drug they received: group one--46 patients on carbamazepine, and group two--100 patients on valproate. Quality of life (QOL) and total costs per patient per year were calculated. QOL was assessed using a questionnaire--Quality of Life in Epilepsy Inventory (QOLIE-31). Costs included direct medical, non-medical and indirect costs related to either epilepsy or its treatment. The assessed demographic and clinical factors were: age, gender, type of seizures, number of registered adverse events (AE) per three months, interval between seizures and seizure reduction percentage. RESULTS AND CONCLUSIONS: In both groups, age, gender and type of seizures didn't cause significant differences in the formation of QOL and costs. In the carbamazepine patients costs were influenced by the incidence of AEs, the time between seizures and seizure reduction percentage. In the valproate patients costs were mainly influenced by the time period between seizures while QOL by the incidence of AEs.

A pharmacoeconomic comparison of monotherapy with Tegretol, Finlepsin and Trileptal (preliminary data).

AIM: Pharmacoeconomics comprises a system of relatively new methods that inform policy makers about the costs and benefits of different therapies so that limited health care resources may be allocated efficiently. The purpose of this study was to perform a pharmacoeconomic comparison of three of the most widely used antiepileptic drugs in Bulgaria: carbamazepine (two different products: Tegretol and Finlepsin) and oxcarbazepine (Trileptal). PATIENTS AND METHODS: The inclusion criteria for entering the study were: women or men of age with newly detected and clinically diagnosed epilepsy,monotherapy treatment with the studied drugs, ability to keep personal records. The follow-up visits were conducted in three-month periods, each visit including a thorough evaluation of effectiveness, costs and quality of life. Effectiveness was assessed as seizure reduction percentage and time till new seizure. Costs included direct and indirect medical and nonmedical costs, related to epilepsy or its treatment. The quality of life of the patient was assessed with Quality of Life in Epilepsy Inventory 31 (QOLIE)--an evaluation instrument accepted for use in clinical practice. The statistical methods used included: descriptive analysis, Pearson correlation and Kaplan-Meyer analyses. RESULTS: The mean seizure reduction was 86.05% for Finlepsin, 83.31% for Tegretol and 66.67% for Trileptal. There were no seizure-free patients on Trileptal, while almost 60% of Tegretol and nearly 50% in Finlepsin patients remained seizure-free for a period of one year. CONCLUSIONS: The quality of life of all patients was high, indicating good efficacy and safety as assessed by patients. There was a significant difference in terms of costs in the Trileptal group compared with the other two groups --it incurred higher annual costs as well as higher cost-per-QALY value.