Continuous innovation in the drug life cycle

Patients may benefit from new uses for old drugs. Competent authorities such as the European Medicines Agency evaluate the quality, efficacy and safety of a medicinal product for the use in a well-defined therapeutic indication. Innovations may continue upon the approval, for example through the licensing of new therapeutic indications or dosage forms, which is also known as post-innovation innovation. The development of new therapeutic indications for existing drugs, could allow for a quicker and cheaper drug development by the utilisation of existing knowledge. The aim of the present thesis was to provide insight in the performance of the drug regulatory system for medicines in the post-innovation phase of their life cycle. Special interest has been paid to the period after the approval of the first generic product version of a drug: the post-generic phase. That occasion may significantly affect the intellectual property prospects of a drug and may limit the opportunities to make a return on investments for further innovations. First, we showed through two studies that in the European Union’s Decentralised Procedure and the Mutual Recognition procedure, which are frequently used to obtain approval for generic medicinal products, licensing failure occurred in about 1 out of 10 licensing procedures. The reasons for licensing failure varied widely and were both of a drug quality and clinical nature. It was also concluded that increased knowledge at the level of companies and regulators has reduced the frequency of late-stage failure of marketing applications via both procedures. Subsequently, we studied to what extent the drug regulatory system allowed for innovation during the post-innovation phase of the drug life cycle. We showed that extensions of the indication of already licensed medicinal products were mainly authorised a few years before approval of the first generic product version and ceased thereafter. On the contrary we found that old drugs were licensed as new medicinal products approved for new therapeutic indications or other innovations. A case study indicated that the viability of the business case for the development of such medicines may depend on a specific window of opportunity within a therapeutic area and the possibility to establish a period of relative exclusivity. We also demonstrated that after approval of a first generic product version the number of clinical trials with those drugs decreased but a considerable amount of clinical research still remained. Our analysis of the EU legislation and case-law of the European Court of Justice showed that the need for prior market approval has consistently been considered to be the general rule of the EU legislation on medicinal products; also for post-innovation innovation. However, we observed a clinical need for unlicensed pharmacy preparations and off-label use, while there are even more potential new uses. These observations in combination with society’s struggle with the need to license new uses of existing drugs and the lack of adequate incentives to do so, suggests that the drug regulatory system is under pressure. Regulatory reform is needed to enhance post-innovation innovation and use every drug to its full potential.