Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The Clinical Development of Disease-Modifying Therapies for Multiple Sclerosis: Critical Overview of the Regulatory Requirements based on the Revised Guideline EMA/CHMP/771815/2011, Rev.2 ***

Dr. Franziska Pirkl (Abschlußjahr: 2015)

Summary
Language: English
The most common demyelinating disease in highly developed countries is multiple sclerosis (MS). It is a very heterogeneous disease with a wide spectrum of neurological symptoms including problems with mobility, vision, and coordination, as well as cognitive dysfunction, fatigue, pain and mood disorders. Different forms exist which are either characterised by the occurrence of acute relapses (RRMS), or by increasing disability with or without superimposed relapses (progressive MS). Depending on when it occurs, progressive MS is classified as primary progressive (PPMS) or secondary progressive (SPMS). In 2013, MS affected 33 per 100,000 people globally. The average age of MS onset is 30 years and it occurs more often in women than in men. Its cause is multifactorial and is thought to involve bothenvironmental exposure and genetic susceptibility. Despite all efforts, the mechanisms that lead to progressive MS seem to be far less well understood than those that contribute to the relapsing forms.
The past decades have seen tremendous progress in the treatment of MS with the introduction of effective drugs for RRMS and to date 12 disease-modifying treatments are available in various countries. Of these, 10 have been granted a central marketing authorization in the European Union. However, similar success has not been seen for PPMS and SPMS.
Recently, the European Medicines Agency (EMA) issued the second revision of its guideline on clinical investigation of medicinal products for the treatment of MS (EMA/CHMP/771815/2011, Rev. 2). The focus of this revised guideline is on treatments that modify disease progression. These treatments usually require long-term superiority trials versus placebo or active comparator. However, as long as issues concerning assay sensitivity can be properly addressed, non-inferiority studies are also an option. In general, assessments of relapse and disability progression are the most important endpoints. In the revised guideline, the time to relapse has been added as an acceptable primary endpoint and clinical global assessment and patient reported outcomes have been added as secondary endpoints.
Despite its known shortcomings, the Expanded Disability Status Scale (EDSS) remains the only validated outcome measurement for disability in the revised guideline. However, the revised guideline acknowledges the need for alternative scales that assess disability and encourages their development. Additionally, it stresses the need for developing patient reported outcome measures.
For claims concerning disability, a study duration of about 3 years is suggested and an extended follow-up (e.g. 5 years or even longer) is recommended, which might also be performed post-approval. The data generated should allow for separate benefit risk assessments for the different degrees of disease activity.
Additional specifications concerning symptomatic treatment of impairments in motion and mobility, visual acuity, pain, or fatigue, have been added in the guideline revision. In this context, randomised placebo-controlled trials are also required focussing on the improvement of stable residual impairment. As the objectives of symptomatic treatment can be very divergent, the revised guideline does not make any further specific recommendations apart from stating that the scales used should be appropriate to the condition studied.
Taken together, the revised guideline maintains an open approach concerning a number of aspects such as potential alternatives to the EDSS or other outcome measures, arguing that these scales and measures are still under development and need to be validated first.
With regard to these questions, sponsors should seek early interaction with the authorities, particularly scientific advice and biomarker qualification procedures, in order to obtain the most up-to-date position of the EMA on the respective issues.
Pages: 73, Annexes: 1 (5 Tables)