An analysis of marketing authorisation applications via the mutual recognition and decentralised procedures in Europe.

PURPOSE: The aim of this study is to provide a comprehensive overview of the outcomes of marketing authorisation applications via the mutual recognition and decentralised procedures (MRP/DCP) and assess determinants of licensing failure during CMDh referral procedures. METHODS: All MRP/DCP procedures to the Co-ordination group for Mutual recognition and Decentralised procedures-human (CMDh) during the period from January 2006 to December 2013 were analysed. Reasons for starting referral procedures were scored. In addition, a survey under pharmaceutical companies was performed to estimate the frequency of licensing failure prior to CMDh referrals. RESULTS: During the study period, 10392 MRP/DCP procedures were finalized. Three hundred seventy-seven (3.6%) resulted in a referral procedure, of which 70 (19%) resulted in licensing failure, defined as refusal or withdrawal of the application. The frequency of CMDh referrals decreased from 14.5% in 2006 to 1.6% in 2013. Of all referrals, 272 (72%) were resolved through consensus within the CMDh, the remaining 105 (28%) were resolved at the level of the CHMP. Most referrals were started because of objections raised about the clinical development program. Study design issues and objections about the demonstration of equivalence were most likely to result in licensing failure. An estimated 11% of all MRP/DCP procedures resulted in licensing failure prior to CMDh referral. CONCLUSION: Whereas the absolute number of MRP/DCP procedures resulting in a referral has reduced substantially over the past years, no specific time trend could be observed regarding the frequency of referrals resulting in licensing failure. Increased knowledge at the level of companies and regulators has reduced the frequency of late-stage failure of marketing applications via the MRP/DCP.

Licensing failure in the European decentralised procedure.

The majority of the licensing applications in the European Union are submitted via the decentralised procedure. Little is known about licensing failure (i.e. refusal or withdrawal of a marketing authorisation application) in the EU decentralised procedure compared to the EU centralised procedure and the approval procedure in the United States. The study aim was to determine the frequency of and determinants for licensing failure of marketing authorisation applications submitted via this procedure. We assessed procedures that failed between 2008 and 2012 with The Netherlands as leading authority and assessed the remaining major objections. In total 492 procedures were completed, of which 48 (9.8%) failed: 8 refused, 40 withdrawn. A wide variety of major objections was identified and included both quality (48 major objections) and clinical (45 major objections) issues. The low failure rate may be related to the regular interaction between competent authorities and applicants during the procedure. Some degree of licensing failure may be inevitable, as it may also be affected by the financial feasibility or willingness to resolve major objections, as well as other reasons to withdraw an application besides the raised major objections.

Extensions of indication throughout the drug product lifecycle: a quantitative analysis.

The marketing authorisation of the first generic product version is an important moment in a drug product lifecycle. The subsequently changed intellectual property protection prospects could affect the incentives for further drug development. We assessed the quantity and nature of extensions of indication of small molecule medicinal products authorised through the European Medicines Agency throughout the drug product lifecycle with special attention for the impact of the introduction of a first generic competitor. The majority (92.5%) of the extensions of indication was approved during the exclusivity period of the innovator product. Regulatory rethinking might be needed for a sustainable stimulation of extensions of indications in the post-generic period of a drug product lifecycle.

Drug repositioning and repurposing: terminology and definitions in literature.

Drug repositioning and similar terms have been a trending topic in literature and represent novel drug development strategies. We analysed in a quantitative and qualitative manner how these terms were used and defined in the literature. In total, 217 articles referred to 'drug repositioning', 'drug repurposing', 'drug reprofiling', 'drug redirecting' and/or 'drug rediscovery'. Only 67 included a definition ranging from brief and general to extensive and specific. No common definition was identified. Nevertheless, four common features were found: concept, action, use and product. The different wording used for these features often leads to essential differences in meaning between definitions. In case a clear definition is needed, for example from a legal or regulatory perspective, the features can provide further guidance.