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Summary
There are currently six approved disease-modifying therapies available to the physician
for the treatment of multiple sclerosis. Their efficacy on clinical and radiological
parameters has been demonstrated in Phase III pivotal clinical trials over the past
two decades. Perceptions of the relative potency of these treatments have been driven
principally by the response measured relative to a placebo group. However, efficacy
comparisons between trials is of limited value because of differences in study methodology,
in characteristics of the patient populations included, in the behaviour of the placebo
group during the trial and in the time at which the trial was conducted. Moreover,
and most importantly, the assumption that the efficacy observed in clinical trial
settings is the same as that achievable in everyday clinical practice is inevitably
flawed. Impressions of the relative efficacy of two treatments may differ dramatically
depending on whether absolute or relative differences with respect to placebo are
compared. Randomised direct comparative trials are therefore the only objective way
to evaluate the relative efficacy of two therapies. It is clear that between-treatment
differences are difficult to quantify in short-term studies and require large numbers
of patients. Long-term outcome is increasingly important to monitor in spite of the
inherent methodological limitations in order to establish the safety profile of a
potentially lifelong treatment. New disease-modifying treatments for multiple sclerosis
will soon be available. Although these are eagerly awaited, their risk–benefit profile,
and their place in therapy, will only be adequately understood once real-life and
long-term use has been documented as well as it has been for current treatments.
Over the last two decades, considerable advances have been made in the methodology
of clinical trials in multiple sclerosis. Consensual standardised protocols have been
designed and validated for Phase II and Phase III trials, with standardised definitions
for short-term clinical and radiological outcome measures. The elaboration and implementation
of this methodology were possible through international collaborations, and this has
enabled extensive experience to be gained throughout the world. These trials have
laid the foundation for an evidence-based medicine approach to the treatment of multiple
sclerosis.
Clinical trials in multiple sclerosis have to some extent become a victim of their
own success, with more and more trials competing for a limited pool of patients and
limited resources. Modern trials require large number of patients to generate adequate
statistical power and this in turn entails recruitment in many countries across different
continents. This increases the complexity and cost of the study, and contract research
organisations now play a dominant role in the logistics and administration of these
trials.
The challenge in conducting trials on a global basis involving large numbers of countries
is to ensure that this heterogeneity does not impinge on the reliability of the findings.
This may happen due to differences in the patient populations included in different
countries, access to or experience with methods in evaluation, for example certain
magnetic resonance imaging (MRI) protocols, and also due to ethical considerations.
In addition, whether disease-modifying treatments are reimbursed in a given country
or not will influence what sort of patients are likely to get included in clinical
trial protocols.
Keywords
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References
- Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study.Neurology. 2004; 63: 1788-1795
- Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis.Lancet. 1998; 352: 1491-1497
- Randomized controlled trial of interferon-beta-1a in secondary progressive MS: Clinical results.Neurology. 2001; 56: 1496-1504
- Benefit of interferon beta-1a on MSFC progression in secondary progressive MS.Neurology. 2002; 59: 679-687
- Secondary progressive multiple sclerosis: current knowledge and future challenges.Lancet Neurol. 2006; 5: 343-354
- Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial.Lancet. 2002; 360: 2018-2025
- A comparison of observational studies and randomized, controlled trials.N Engl J Med. 2000; 342: 1878-1886
- Randomized, controlled trials, observational studies, and the hierarchy of research designs.N Engl J Med. 2000; 342: 1887-1892
- Systematic reviews in health care: Assessing the quality of controlled clinical trials.BMJ. 2001; 323: 42-46
- Should meta-analyses of interventions include observational studies in addition to randomized controlled trials? A critical examination of underlying principles.Am J Epidemiol. 2007; 166: 1203-1209
- Copolymer 1 reduces relapse rate and improves disability in relapsing–remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group.Neurology. 1995; 45: 1268-1276
- Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate.Mult Scler. 2010; 16: 342-350
- A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.N Engl J Med. 2010; 362: 416-426
- The changing demographic pattern of multiple sclerosis epidemiology.Lancet Neurol. 2010; 9: 520-532
- Prevalence of multiple sclerosis in Denmark 1950–2005.Mult Scler. 2010; 16: 520-525
- Problems of experimental trials of therapy in multiple sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis.Ann N Y Acad Sci. 1965; 122: 552-568
- New diagnostic criteria for multiple sclerosis: guidelines for research protocols.Ann Neurol. 1983; 13: 227-231
- Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.Ann Neurol. 2001; 50: 121-127
- Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”.Ann Neurol. 2005; 58: 840-846
- MRI criteria for MS in patients with clinically isolated syndromes.Neurology. 2010; 74: 427-434
- The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer.N Engl J Med. 1985; 312: 1604-1608
- Will Rogers phenomenon in multiple sclerosis.Ann Neurol. 2008; 64: 428-433
- Assessing changes in relapse rates in multiple sclerosis.Mult Scler. 2010; 16: 1414-1421
- Efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis: a systematic comparison.Eur Neurol. 2008; 60: 1-11
- Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).Ann Neurol. 1996; 39: 285-294
- Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis.Lancet. 1998; 352: 1498-1504
- Interferon beta-1b is effective in relapsing–remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group.Neurology. 1993; 43: 655-661
- A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.N Engl J Med. 2006; 354: 899-910
- A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.N Engl J Med. 2010; 362: 387-401
- Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial.Lancet Neurol. 2008; 7: 903-914
- 250 mug or 500 mug interferon beta-1b versus 20 mg glatiramer acetate in relapsing–remitting multiple sclerosis: a prospective, randomised, multicentre study.Lancet Neurol. 2009; 8: 889-897
- Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.N Engl J Med. 2010; 362: 402-415
- Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis. NICE, London2007
- MRI measures of neuroprotection and repair in multiple sclerosis.J Neurol Sci. 2011; 311: S16-S23
- Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta.Proc Natl Acad Sci U S A. 2004; 101: 8705-8708
- Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis.Proc Natl Acad Sci U S A. 2006; 103: 5941-5946
- Freedom from disease activity in multiple sclerosis.Neurology. 2010; 74: S3-S7
- New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab.Lancet Neurol. 2009; 8: 28-31
- Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.Neurology. 2010; 74: 1463-1470
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© 2011 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
