Purpose Pharmaceutical innovation is not only about finding new drugs but also about enhancing existing ones. This study aims to explore the role of hybrid applications as a regulatory route in the framework of the European Medicines Agency (EMA) for incremental innovation through changes to authorized reference products. Design/methodology/approach A systematic review of the literature was undertaken carrying out search on PubMed, Scopus, Google Scholar articles along with white and business papers from official websites. The review concentrated on hybrid applications from publications and regulatory documents of 42 studies, European Union regulatory frameworks and innovations that were conducted between 2000 and 2025. Relevant data was organized and arranged systematically into case studies, efficiency, limitations, regulatory and future perspectives. Findings Hybrid applications provide an intermediate regulatory pathway between generic and full applications. They allow developers to capitalize on prior data and submit new nonclinical or clinical data to support changes in indication, formulation or delivery route. Some case studies analyzed illustrate hybrid uses as effective mechanisms for advancing therapies and enhancing patient access. However, it is not without its challenges. Some of these include complicated bridging data needs, regulatory ambiguity and restricted market exclusivity. Achievement is heavily reliant upon initial scientific counsel, strategic planning for development and sound risk handling. Originality/value The review highlights the strategic value of hybrid applications in promoting therapeutic innovation within regulatory frameworks, safety, regulatory efficiency, striking a balance between innovation and efficacy of the European pharmaceutical domain.
KM et al. (Fri,) studied this question.