Background: Mature products (MPs - marketed for 10 years or more) are widely used off label (from 15 to 35% according to studies) despite little evidence on benefit risk ratio. This exposes patients to risks or lack of efficacy and healthcare providers to liability. However manufacturers are rarely investing in R&D development for MPs.  Indeed MPs face price cuts in Europe, whether due to generic competition, price negotiations or inclusion in reference price groups. Moreover new indications, even if demonstrating a higher value of the drug, often lead to price reductions in Europe due to a combination of price/volume agreements and external reference pricing. Products are included in reference price groups even for a new indication. While reference price groups only include off-patent drugs in France and Italy, these groups may include patented drugs in Spain (if older than 10 years) and Germany.There are significant disincentives for manufacturers to invest in R&D for MPs, preferring instead to develop new molecular entities rather than unlocking the full therapeutic potential of MPs. This is especially the case for small populations (rare and ultra-rare diseases) where there is high unmet medical need and MPs could offer cost-effective solutions with known safety profiles. Discussion: The development of new indications for MPs can be a win-win solution for patients and payers. It offers an alternative to off label or lengthy and expensive development of new therapies, as well as more equity in patients’ access to treatment. As safety accounts for approximately 30% of drug failures in clinical trials, mature products can also offer a quicker and less expensive access to therapy, especially in areas of high unmet need. Conclusion: Incentives for orphan drugs or pediatric indications have proven to be effective in promoting R&D. New incentives should be developed to promote R&D in MPs.