Illustration of patient-reported outcome challenges and solutions in rare diseases: a systematic review in Cushing's syndrome.

Rare diseases are often not fully understood and efforts put in investigating it from patient perspective are usually met with challenges. We performed a systematic literature review (SLR) for the last 20 years in Cushing's Syndrome (CS) to illustrate Patient-Reported Outcome (PRO) challenges, and show what solutions were found.PROs and other Clinical Outcome Assessment (COA) used with CS patients were reviewed in 36 studies. Two CS-specific Health Related Quality of Life (HRQL) measures were identified (i.e., CushingQoL, Tuebingen CD-25), as well as depression and neurocognitive measures. For CS-specific HRQL measures, the CushingQoL was the most widely used measure due in part to being the first CS-specific HRQL measure developed. With algorithms mapping the CushingQoL to both the SF-6D and EQ-5D, the CushingQoL could be used to facilitate economic modelling studies in the absence of a generic HRQL measure. While the CushingQoL offers only the global scale and two subscales compared to the six subscales of the Tuebingen CD-25, there is not yet adequate statistical validation data available for the Tuebingen CD-25 to suggest it can withstand the scrutiny of review by multiple stakeholders. Results of this review indicate that the inclusion of a measure of depressive symptoms, such as the BDI-II or similar measure, would be reasonable to include given the high level of comorbidity of depression among CS patients. A brief neurocognitive performance outcome, such as Trail Making tasks A and D or Digit Symbol, could help inform the interpretation of HRQL results. Neurocognitive differences may be an unassessed mediator of HRQL outcomes, partly accounting for the persistence of depressive symptoms and HRQL deficits despite treatment. Results suggest that HRQL improvements are possible within this population. These results are limited by small sample sizes and pre/post study design.CS showcases the difficulties encountered in measuring PROs in rare diseases. A solution for this specific case was developed in the form of dedicated PRO instruments, the CushingQOL and the Tuebingen-25. However, some aspects of CS may not be fully answered or not yet validated (e.g., depressive and cognitive symptoms). Further research needs to be done to address them.

Unlocking the potential of established products: toward new incentives rewarding innovation in Europe.

Background: Many established products (EPs - marketed for eight years or more) are widely used off-label despite little evidence on benefit-risk ratio. This exposes patients to risks related to safety and lack of efficacy, and healthcare providers to liability. Introducing new indications for EPs may represent a high societal value; however, manufacturers rarely invest in R&D for EPs. The objective of this research was to describe incentives and disincentives for developing new indications for EPs in Europe and to investigate consequences of current policies. Methods: Targeted literature search and expert panel meetings. Results: Within the current European-level and national-level regulatory framework there are limited incentives for development of new indications with EPs. Extension of indication normally does not allow the price to be increased or maintained, the market protection period to be extended, or exclusion from a reference price system. New indication frequently triggers re-evaluation, resulting in price erosion, regardless of the level of added value with the new indication. In consequence, manufacturers are more prone to undertake R&D efforts at early to mid-stage of product life cycle rather than with EPs, or to invest in new chemical entities, even in therapeutic areas with broad off-label use. This represents a potentially missed opportunity as developing new indications for EPs offers an alternative to off-label use or lengthy and expensive R&D for new therapies, opens new opportunities for potentially cost-effective treatment alternatives, as well as greater equity in patients' access to treatment options. Conclusion: There are potential benefits from the development of new indications for EPs that are currently not being realized due to a lack of regulatory and pricing incentives in Europe. Incentives for orphan or paediatric drugs have proven to be effective in promoting R&D. Similarly, incentives to promote R&D in EPs should be developed, for the benefit of patients and healthcare systems.