Marketing authorisation of new medicines in the EU: towards evidence-based improvement

The relevance of continuous development of new medicines is publicly recognized, but the development of new medicines requires increasing efforts and costs. Despite regulatory initiatives to enhance marketing authorisation such as the orphan regulation and the scientific advice procedure, current non-approval rates of new medicines are relatively high, varying from 25-40%. In order to further improve the EU marketing authorisation system there is a need for empirical studies to gain insight in the way benefits and risks are evaluated and approval decisions are made by regulatory authorities. This thesis offers empirical analyses of approval decisions and the scientific advice procedure to facilitate future evidence-based improvement of the regulatory system. First, we assessed to what extent the design of the development plan, the clinical outcomes and clinical relevance of new active substances in the EU according to the European Medicines Agency (EMA) Committee for Medicinal Products for Human use, were associated with non-approval. This study demonstrated that disappointing clinical efficacy and safety outcomes were the major driver for non-approval (odds ratio (OR) 21.7; 95% confidence interval (CI) 5.0–94.0). Non-convincing clinical relevance contributed less to the likelihood of non-approval (OR 4.6; 95% CI 1.1–20.0) than a disappointing clinical outcome. Conversely, positive scores on clinical relevance can help overcome deficiencies with regard to clinical outcome, particularly when good alternative treatment options are lacking for the disease. In addition, we demonstrated the relevance of the underlying development plan (exploratory and confirmatory) for increasing the likelihood that a medicinal product is approved (OR 6.1; 95% CI 0.9–42.7). Relevant exploratory studies of the mode of action, proof of concept and dosing are valuable in reducing the number of failed dossiers and speeding up pharmaceutical innovation. Drug developers are encouraged to increase investments in such studies before moving to large and more costly Phase III trials. We also compared orphan medicinal products (OMPs) and non-OMPs and found differences in regulators´ concerns related to the clinical development plan (study design), related to clinical outcome (safety profile), and related to acknowledged high medical need. But overall these differences did not result in differential weighing of the benefit-risk for marketing approval. Our results encourage future OMP developers to search for opportunities to meet the high standards of clinical drug development e.g. for comparative study designs and validated clinically relevant endpoints. Secondly, we evaluated the role of the scientific advice procedure. An interview study with Dutch small and medium-sized enterprises demonstrated that their aims of scientific advice were to retrieve regulators’ reassurance of their development plan, to gain regulators’ trust and to a lesser extent to fill knowledge gaps where guidelines are lacking or unclear. An overview of scientific advice questions discussed with the Dutch Medicines Evaluation Board in the period 2006–2008 demonstrated that large companies considered the phase III trial package most relevant to discuss with regulators, whereas small companies more often aimed to discuss early drug development. The relevance of an appropriate development plan for marketing approval implies that scientific advice about exploratory and confirmatory development plans earlier and continuously during drug development could increase approval rates