Challenges in drug development for central nervous system disorders: a European Medicines Agency perspective

Drug development for central nervous system (CNS) disorders is challenging, and a higher attrition rate compared with non-CNS drugs has been reported (Nat. Rev. Drug Discov. 14, 815–816; 2015). With the aim of improving the understanding of these challenges, we analysed the clinical development programmes reviewed by the European Medicines Agency (EMA) for both a new approval and a new indication of an already approved product in psychiatry and neurology. In total, we identified 103 applications (57 in neurology and 46 in psychiatry) that were reviewed by the EMA from 1995 to 2014 (see Supplementary information S1 (box) for details). We investigated the nature of the major clinical issues, as identified by the evidence-based assessment of the data provided to the EMA, which we categorized into four main domains following the drug development path (Fig. 1a). The clinical development programmes in our data set are those for which sponsors put forward a product for approval, which suggests that the sponsor considered them sufficiently successful to have a reasonable chance of approval. However, major uncertainties in the outcome of the drug development programmes were apparent, with efficacy issues identified in more than one-third of programmes, and safety issues in more than half of programmes. Moreover, problems such as unclear or missing clinical proof-of-concept, dose-finding or pharmacokinetics and pharmacodynamics (PK/PD) studies were reported in more than one-third of the clinical programmes reviewed in psychiatry (37%) and almost half in neurology (46%). In the subset of applications that had major problems with study outcome (efficacy or safety), more than half (54%) also had problems in the early clinical development phase, whereas this was the case in only 13% of applications that did not show any major outcome issues (odds ratio (OR) = 7.8, 95% confidence interval (CI) = 2.4–33.9). Furthermore, 91% of development programmes that had problems related to the early phases also had issues at a later phase (efficacy or safety), whereas later phase issues occurred in only 55% of those that did not have problems in the early phases. In particular, there was a strong association between shortcomings identified in PK and drug–drug interaction studies and concern over the safety profile (OR = 4.1, 95% CI = 1.4–14.1) and between dose finding and clinical outcome as a whole (OR = 5.9, 95% CI = 1.3–55.4). We found also some important differences between the two therapeutic areas of interest. In psychiatry, issues with planning — in particular, related to the study hypothesis and selection of the population — were more common than in neurology (respectively, 28% versus 9%, OR = 4.0, 95% CI = 1.2–15.9) and 60% versus 24%, OR = 4.7, 95% CI = 1.9–12.2). The two issues are linked, as an inappropriate study hypothesis is likely to lead to an inadequate selection of population. Indeed, we found a tenfold increased risk of having issues with the recruited population (such as inappropriate inclusion criteria) when the study hypothesis was not clear (OR = 10.5, 95% CI = 2.7–61.2). The definition and classification of disorders and hence the selection of the patient population are challenging in psychiatric indications such as major depressive disorder because of the heterogeneity of the clinical presentation. Furthermore, concerns about the effect size, and/or the potential clinical benefit of the investigational drugs were also more commonly reported in psychiatry than in neurology (respectively 30% versus 10%, OR = 3.7, 95% CI = 1.2–12.9), and 57% versus 25%, OR = 3.9, 95% CI = 1.6–10.1). We also investigated how and to what extent these issues may have influenced the outcome of the applications (see Supplementary information S1 (box) for details). Selection of the population, clinical benefit, safety and dose selection were among the issues with the strongest impact on the outcome of applications in psychiatry, whereas issues such as failure to reach the primary end point, safety and lack of properly conducted specific PK/PD studies were among those with the strongest impact on the outcome of applications in neurology (Fig. 1b).In summary, our findings indicate some differences in the types of challenge for drug development for neurology and psychiatry indications and also highlight the importance of the design of early-stage clinical trials. The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or one of its committees or working parties. The authors are grateful to M. Berntgen for his support in this project and would also like to thank O. Collignon for advice on the statistical methodology.