Background The EMA's Committee for Medicinal Products for Human Use (CHMP) prepares scientific guidelines in consultation with regulatory authorities in the EU Member States, to help applicants prepare marketing-authorisation applications for human medicines, including rheumatology. These guidelines are developed by the RIWP, which is composed of European experts selected from or associated with national agencies.
Objectives The current EMA Guideline on rheumatoid arthritis (RA) dates from 2003. Ever since, there has been a major change in treatment paradigm of RA, with treatment to target in an earlier disease phase. These advancements require modified recommendations regarding the development of RA therapies.
Methods Development and release for consultation of the concept paper by RIWP.
All external comments received are currently reviewed and the draft guideline will be amended as required before release of the final guideline by the CHMP.
Results New primary endpoints were defined, reflecting treatment targets of low-disease activity (LDA) or even remission, in place of the previous primary endpoint of ACR20 scores. Furthermore, a distinction is made in the design and endpoints for DMARD naïve patients, where a DAS28-ESR score <2.6 is considered as a realistic target, or patients irresponsive to MTX or a biological DMARD, where a DAS28 score <3.2 is considered as an acceptable endpoint. For patients with long-standing disease irresponsive to multiple DMARDs, ACR20 is still considered a suitable primary endpoint. For the main study, a three-arm trial including placebo and an active comparator is required. For ethical reasons, placebo may be as short as 6–12 weeks, using rescue medication. Alternatively, superiority of the new product may be shown to an active comparator in a two-arm study.
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. According to this updated guideline, maintenance of remission and LDA could serve indirectly as an indicator for the prevention of structural damage, provided that routine monitoring by X-ray do not indicate a deviating trend as compared to an established comparator treatment. Considering the challenges of demonstrating structural damage regarding power, non-inferiority does not need to be demonstrated formally.
Conclusions The EMA guideline on the development of products in the treatment of RA, has undergone some major revisions regarding endpoints and study design, in accordance to current European clinical practice.
draft Guideline on clinical investigation of medicinal products other than NSAIDs for treatment of rheumatoid arthritis CPMP/EWP/556/95 Rev. 2. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/06/WC500187583.pdf/p>
Disclosure of Interest None declared