Fri0609 european medicines agency's guideline on the clinical investigation of medicinal products for the treatment of rheumatoid arthritis
Authors: D. Da Silva, E. Rook, N. Semis-Costa, J. Mueller-Berghaus, R. Vesely
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> The European Medicines Agency (EMA) in consultation with regulatory authorities in the EU Member States prepares scientific guidelines, to help drug developers prepare marketing authorisation applications. The scope of the rheumatoid arthritis (RA) guideline is to provide a European common position on the clinical evaluation of new medicinal products. <h3>Objectives:</h3> The EMA guideline is an update of the Points to Consider adopted in 2003. A revision of the guideline was required as the pharmacological therapy of RA has advanced. Treat-to-target strategies are now employed, and the optimum treatment goal is remission, or at least low disease activity (LDA). New classification criteria for RA have been developed and validated by the ACR-EULAR, which allows for earlier DMARD use. Increasing knowledge of the risk associated with DMARDs has been gained from trials and registries. <h3>Methods:</h3> The guideline has been prepared by the Rheumatology-Immunology Working Party of the EMA. The guideline was revised based on literature, and recent trial and safety data from regulatory dossiers of RA products. External experts, investigators, industry and patient representatives were consulted ("Public consultation"), and in person during a Targeted consultation meeting in 2016. <h3>Results:</h3> New primary endpoints (PE) were defined, reflecting treatment targets LDA or remission, in place of the previous PE of ACR20. Different validated scales may be used (either DAS28-ESR, DAS28-CRP, SDAI, or CDAI). The PE of choice should be corroborated by other outcomes as secondary endpoints. E.g if DAS28-CRP is chosen, more stringent outcomes like SDAI and DAS-ESR, or CDAI, which is independent of biomarkers CRP or ESR, should point at the same direction. A distinction is made between study populations of DMARD naïve patients, where remission at 3 months is considered as a realistic target and methotrexate a suitable comparator; and patients irresponsive (or insufficiently responsive) to prior DMARDs, where LDA at 3–6 months is considered as an acceptable endpoint. For patients with long-standing disease irresponsive to multiple DMARDs, including two biologic DMARDS of different classes, ACR20 is still acceptable. Long-term safety data of 12 months should be available before marketing authorisation. The ultimate goal of RA treatment is the prevention of structural joint damage. However, showing an effect on structural damage has become increasingly challenging, since the placebo control should be kept short, and milder or more controlled patients may be eligible for studies of new DMARDs. Therefore, maintenance of remission and LDA could serve indirectly as an indicator for the prevention of structural damage, provided that these clinical outcomes are compelling, and routine monitoring by X-ray does not indicate a deviating trend as compared to an established comparator. <h3>Conclusions:</h3> The EMA guideline on the development of products in the treatment of RA has undergone major revisions regarding the choice of endpoints and study design. The revision comes into force in July 2018. <h3>Reference</h3> 1. Guideline on clinical investigation of medicinal products for the treatment of rheumatoid arthritis14December 2017. [CPMP/EWP/556/95 Rev. 2] http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2018/01/WC500241042.pdf <h3>Disclosure of Interest:</h3> None declared