Regulator's view on the scientific and regulatory challenges in new mobility outcomes & PROs

The current focus from research based pharmaceutical companies is rather on cancer, not CNS. There are several reasons for this, e.g. problems with pre-clinical models, problems with dose-finding, large long-lasting trials, high failure rate, eventually leading to no return on investment. Are the regulatory requirements too high? Certainly not in Multiple Sclerosis, where we had 5 approvals since 2011 (Fingolimod, Fampridine, Teriflunomide, Alemtuzumab, Dimethylfumarate). In parallel we have worked on a new guideline for MS clinical trials, starting with a concept paper in 2011 followed by a large EMA workshop with all relevant stakeholders in 2013. The aim was "to make sure that in the revision of the MS guideline, the EMA can take the most up-to-date, state-of the-art scientific developments in MS into consideration, as well as the positions of experts in the field on the main topics in the guideline". The publication of the final guideline followed in Q2 in 2015 (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/03/WC500185161.pdf). Among other things, we concluded that in the context of long-term outcomes the development of secondary progression is most important. Neither a relapse-based primary endpoint nor an MRI based endpoint can be accepted as a surrogate for disease progression. The EDSS as a rating scale for disability is widely used but has well-known deficiencies, e.g. considerable variability among assessors, that make the interpretation of clinical relevance difficult. However, MS specialists and regulators are familiar with EDSS and it is historically the most frequently used clinician assessment of neurologic impairment in MS clinical trials. Therefore it still will be important to use the EDSS, along with other candidate parameters, to assess true unremitting disability also in future trials to allow comparison among trials. Candidates for other parameters to assess disability are various short-time functional walking tests (e.g. T25-FW, 6MWT) and the MSWS12. Alternative tools to EDSS are currently being developed. Hereby it is important to apply functional assessments for measuring disability in MS. Specific recommendations are not given, but in general the requirements for new tools are that they are reliable, valid, sensitive to change over time, predictive value for disability progression, clinically meaningful and acceptable by the patient. EMA strongly encourages the development of new approaches and innovative methods. EMA intends to apply a flexible approach with regard to the acceptability of positive new endpoints, but a prerequisite is the scientific justification and adequate validation. Qualification procedures are recommended. Collaborative work will be necessary by academia, industry and regulators to develop criteria for appropriate use of PROs in studies, for instance to help assessing clinical relevance.