In the past few decades, the regulatory system has changed its approach to speed up the assessment and approval of drugs for the treatment of serious and orphan diseases. However, too early assessments may fail to provide solid evidence to define the therapeutic value of drugs and their fair price. As for rare diseases, patients' expectations amplify such criticalities due to the lack of therapeutic alternatives. The revision of the EU regulation on orphan medicinal products represents an opportunity to promote greater integration between the development and approval of drugs with their subsequent access. For this reason, we propose: 1) establishing a process for evaluating the comparative efficacy and quantification of the therapeutic benefit of a drug at a European level, while addressing incentives towards rarer diseases to support their development and marketing; 2) downsizing the impact of orphan drugs on general sustainability, considering that incentives supporting their development and marketing cannot transform them into new 'blockbusters'. In this perspective, a European procurement - initially intended for drugs for ultra-rare diseases - could improve access by all EU countries through simplifying the burdensome procedures for the pharmaceutical industry; 3) enhancing the contribution of post-authorization research from a public-private partnership perspective to steer the development of drugs already approved towards rarer pathologies or mutations of little commercial interest.