Challenges Facing Future Multiple Sclerosis Clinical Trials

Challenges Facing Future Multiple Sclerosis Clinical Trials

Butzkueven Helmut, van der Walt Anneke
Published: BTG - FUTURE DIRECTIONS IN NEUROLOGY
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This article will begin by reviewing the continuing success of clinical trials in identifying new treatments for relapsing–remitting multiple sclerosis (RRMS). However, it is also important to note that this success has also led to a great challenge for the MS trial community: identifying the first disease-modifying treatment for progressive MS. Other important challenges also lie ahead. In the next decade, we will see the arrival of many new therapies for RRMS. These new medications will provide patients and doctors with more choice, but they will also be associated with significant new side effects and complications. Some of these complications may become apparent only with prolonged exposure, well in excess of the time for which patients are observed in randomized clinical trials. It is also unlikely that many of these medications will be compared with each other in randomized head-to-head studies, producing a very significant challenge in the development of evidence-based treatment strategies.

We believe that the worldwide web has the potential to underpin global, comprehensive, long-term safety and efficacy outcome registries, and that emerging statistical tools will allow future treatment comparisons to be conducted using these registries, outside the randomized clinical trial framework. However, we must set the groundwork for these efforts now, so that we can effectively and comprehensively capture the real-world treatment experience for the many new therapies that will become available to us in the near future.

The last decade has seen unprecedented clinical trial activity in the therapeutic areas of RRMS and clinically isolated syndromes (CIS). In many parts of the world, this trial activity has resulted in the addition of mitoxantrone1 and natalizumab2 as second-line treatment options for severe relapsing MS. In addition, recent CIS trials have proved the utility of treatment with interferon-beta (IFN-β)3,4 and glatiramer acetate5 for subgroups of patients with high cerebral T2 lesion load on incident magnetic resonance imaging (MRI). Further studies, including the largest study ever conducted in RRMS,6,7 have compared IFN-β and glatiramer acetate head-tohead and confirmed clinical equivalence.

Many phase II and phase III trial programs for RRMS and CIS are ongoing, with the oral cladribine versus placebo (CLARITY) and the fingolomid versus avonex (TRANSFORMS) studies likely to report their outcomes in the first quarter of 2009.8 The prospect of a safe oral medication for RRMS is greatly anticipated by clinicians and patients alike. Additional candidates include teriflunomide, laquinimod, and fumarate (BG12), all currently in extensive phase III trial programs.8 The monoclonal anti-CD52 antibody alemtuzumab has also recently commenced its phase III trial program. If the superior efficacy that this agent demonstrated in its phase II active comparator trial program (alemtuzumab versus rebif) is replicated, it will become a powerful new therapeutic option for severe RRMS.8,9

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