A white paper on a neurodevelopmental framework for drug discovery in autism and other neurodevelopmental disorders.

In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the 'New Frontiers Meeting' on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies.

Psychiatric diseases moving towards adolescents and children: How much room is there for extrapolation?

Since medicines for psychiatric diseases are often studied in adults first, it would be useful if data from efficacy trials in adults could be extrapolated to children and adolescents. However, it is not sufficient to adapt the adult dosages to achieve systemic exposure levels similar to those effective in adults. This can be done with increasing predictive accuracy but before accepting that the same plasma levels should result in the same efficacy as in adults both the mechanism of action of the drug and the pathophysiology of the disease must be considered. For psychiatric disorders there is often insufficient evidence to support the assumptions for extrapolating efficacy as it is not even always sure that the same diagnostic categories correspond to the same disease in adults and children. Even when the basic biological alteration behind the disorder could be considered the same, the psychodynamic consequences and the role of non-pharmacological approaches to treatment may substantially differ across age groups. These facts, together with the absence of detailed historical data on the actual correlations between paediatric and adult responses for many types of psycho-therapeutic medicines, make it difficult to accept extrapolation as the main proof of efficacy in children and adolescents. A corollary is that since efficacy studies will normally be required, they should not be unduly postponed. For products addressing a medical need with good scientific plausibility, they should be initiated as soon as the anticipated safety concerns can be reasonably managed within the context of a paediatric clinical trial.

Sex as a variable in medicines assessment reports for licensing in the European Union. Can gender bias be excluded?

PURPOSE: To analyse publically available official reports on the evaluation of European Union (EU) registration of new medicines (aimed at diseases affecting both sexes) in order to address the possibility of gender bias. METHODS: Descriptive study reviewing two types of assessment reports corresponding to different EU registration procedures: European Public Assessment Reports (EPARs) for the centralised procedures (399 reports considered from 2001 to 2002 and 2008 to 2009) and Mutual Recognition or Decentralised Public Assessment Reports (MPARs) for the mutual recognition and decentralised procedures (2,704 reports, totality until 2009-inclusive). RESULTS: Two hundred and twenty-four EPARs fulfilled the study criteria. It can be deduced from those EPARs that women participated in at least one clinical trial in 215 (78.5 %) of the reports. In 49(17.9 %) of the EPARs, the study population is explicitly evaluated according to sex, ten (3.6 %) presenting results disaggregated by sex. Most sex-related differences are in safety and pharmacokinetics; six of the 22 cases (72.7 %) of safety differences and nine of the 23 cases (60.9 %) of pharmacokinetic differences are not discussed. In relation to MPARs, only 2,704 out of 15,621 registries (17 %) were published, which casts doubts on the representativity of the available reports. Those published reflect less participation by women than in the EPARs. CONCLUSIONS: From the incomplete sex-related data made public, it is difficult to conclude on the existence of gender bias in the evidence used for the evaluation of new medicines. It certainly cannot be excluded. It is therefore recommended that compliance with existing guidance for publication of reports is increased, so as to transparently reassure on the issue.

Standard and intensive lipid-lowering therapy with statins for the primary prevention of vascular diseases: a population-based study.

PURPOSE: To describe the clinical profile of the patients that initiate statin therapy for the primary prevention of vascular diseases and to investigate the extent to which clinicians use intensive vs. standard regimens. METHODS: A cross-sectional analysis of nationwide individual data regarding individuals ≥ 11 years with a first prescription of statin, recorded between 1 January 2007 and 31 December 2011. Subjects were defined as intensive therapy initiators if a statin dose superior to simvastatin 40 mg (or equivalent dose if different statin) was first prescribed. Multivariable logistic regression models were built for dependent summary variables to evaluate the strength of the association between them and the use of intensive therapy. RESULTS: Overall, 69,737 patients receiving a first prescription of statin for the primary prevention of vascular diseases were identified. Predictors for intensive therapy initiation were male gender (adjusted OR: 1.28; 95%CI: 1.10-1.48), history of hypothyroidism (1.47; 1.17-1.85), current treatment of diabetes (1.18; 1.00-1.41), proteinuria (1.87; 1.12-3.12), age, and year of statin prescription. Modifiable risk factors associated with intensive therapy were elevated tryglicerides (1.63; 1.39-1.91), elevated LDL-C (1.96; 1.69-2.28), obesity (1.25; 1.07-1.47), smoking (1.32; 1.14-1.55), comedication with ezetimibe (3.76; 1.87-7.55), fibrates (1.96; 1.43-2.70) and calcium antagonists in women (1.42; 1.02-1.98). CONCLUSIONS: The use of intensive therapy with statins in primary prevention was not very high in absolute terms, but is increasing considerably. The association between intensive therapy and previous hypothyroidism or its combination with fibrates may raise additional safety and tolerability concerns.

Discovery and development of molecularly targeted drugs: regulatory perspectives.

Registration aims at ensuring that the requirements of quality, safety and efficacy for new medicines are met but how much evidence should be generated before considering that a favourable benefit/risk has been demonstrated may be controversial. Regulatory agencies tend to allow some uncertainty (to be resolved after registration) for potentially needed (as opposed to 'me too') substances for serious diseases and, in order to clarify the requirements, they issue 'guidance' documents. The 'Note for Guidance on Evaluation of Anticancer Medicinal Products in Man' of the European Medicines Agency (EMEA) came into operation in July 2003 but an update is announced by means of a Concept Paper both to address methodological aspects (including in relation to the new mechanisms of anticancer agents) and to integrate the new regulatory framework resulting from the recent Review of the European Legislation on Medicinal Products.