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ARTICLES: M. G. Brown, S. Kirby, C. Skedgel, J. D. Fisk, T. J. Murray, V. Bhan, and I. S. Sketris How effective are disease-modifying drugs in delaying progression in relapsing-onset MS? Neurology 2007; 0: 01.wnl.0000271884.11129.f3v1 [Abstract]

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How effective are disease-modifying drugs in delaying progression in relapsing-onset MS?

Steven R. Brenner, None   (5 February 2008)

Reply from the authors

Murray G. Brown, Sarah Kirby, Chris Skedgel, John D. Fisk, T. Jock Murray, Virender Bhan, and Ingrid S. Sketris   (5 February 2008)

How effective are disease-modifying drugs in delaying progression in relapsing-onset MS? 5 February 2008
Steven R. Brenner, Dept. of Neurology at St. Louis VA Med. Center and Neurology and Psychiatry at St. Louis University St. Louis VA Medical Center, 915 North Grand, St. Louis, MO 63106, None Send Correspondence to journal: Re: How effective are disease-modifying drugs in delaying progression in relapsing-onset MS? SBren20979{at}aol.com Steven R. Brenner, et al.	I read the article by Brown et al. who estimated delay of progression of disability in multiple sclerosis (MS) patients treated with disease-modifying drugs. [1] Data indicating delay of progression utilizing patients treated with disease-modifying treatments as their own controls and comparing treated and untreated stages of the illness can not provide the same significance as data from matched placebo-controlled studies of such medicines which have only indicated trends toward significant effects on delay of progression of disability and not a robust effect of treatment. Matched placebo-controlled trials of disease-modifying medicines are more likely to determine the effect of disease-modifying treatment on progression of disability, although the authors have described their information as real-world effectiveness, based on their experiences in clinical practice. Reviewing their article, there was little effect of treatment on secondary progressive MS, however table 1 indicated such patients were much more disabled, EDSS scale of 4.64 at time of first injection than the relapsing remitting patients who had an EDSS scale of 2.12 at first injection. The better outcome from treatment of relapsing onset patients may indicate disease modifying treatments are more effective when prescribed during earlier stages of disability and lose their effectiveness when treating patients who are more disabled. Lumping all the disease modifying medicines--interferons and Copaxone--may lead to uncertain conclusions as well. Reviewing table 1, SPMS patients were treated primarily with interferon agents (12% Copaxone) while the relapsing remitting and relapsing onset patients patients were treated with larger proportions of Copaxone (25% and 21%). Copaxone has been found to have neuroprotective effects in a model of MS while interferon-beta has not.[2] The greater application of a neuroprotective agent in the relapsing-onset and relapsing-remitting patients may have reduced the outcome of disability in these groups compared with the secondary progressive patients. References 1. Brown MG, Kirby S, Skedgel C, et al. How effective are disease- modifying drugs in delaying progression in relapsing-onset MS? Neurology 2007;69:1498-1507. 2. Maier K, Kuhnert A, Taheri N, et al. Effects of glatiramer acetate and interferon-beta on neurodegeneration in a model of multiple sclerosis: a comparative study. Am J Pathol. 2006;169:1353-1364. Disclosure: The author reports no conflicts of interest.
Reply from the authors 5 February 2008
Murray G. Brown, Capital Health Nova Scotia 5790 University Avenue, Rm 228, Halifax NS Canada B3H 1V7, Sarah Kirby, Chris Skedgel, John D. Fisk, T. Jock Murray, Virender Bhan, and Ingrid S. Sketris Send Correspondence to journal: Re: Reply from the authors murray.brown{at}dal.ca Murray G. Brown, et al.	Dr. Brenner raises important questions. What weight should we give to different types of evidence on disease-modifying drugs (DMDs) that alter MS progression? In particular, what weight should be given to Phase III randomized placebo-controlled efficacy trials (RCTs) for individual DMDs, relative to a Phase IV retrospective observational study that estimates the effectiveness of DMDs as a class, and which uses pre- and post-DMD clinical data to enable treated persons to be their own controls? [1] These Phase III RCTs and our Phase IV study addressed different questions including the safety and efficacy of experimental drugs under controlled conditions, versus the safety and effectiveness of licensed drugs under real world conditions. In addition, different types of evidence were considered including high quality data collected prospectively at frequent and fixed time intervals over relatively short study periods. These data were taken from MS patient volunteers who met study selection criteria prior to random assignment to treatment and control groups, versus representative population-based clinic-visit data collected over many years at irregular time intervals from patients that chose DMD treatment when available and whose pre-DMD natural history served as control data. Finally, different estimation methods were used. To conclude, Phase III RCT evidence of efficacy and our Phase IV evidence of DMD effectiveness are complementary. Dr. Brenner observes that our real world evidence indicates DMDs are more effective during earlier stages of MS which our unpublished sensitivity analysis confirms. Dr. Brenner also cautions that estimating effectiveness of DMDs as a class may lead to uncertain conclusions. We agree. But considering the limitations of observational data, we concluded it was preferable to estimate real world effectiveness for DMDs as a class before proceeding to the more challenging task of estimating effectiveness for particular DMDs. This approach enabled estimation of annual EDSS progression prior to treatment, during first DMD treatment years, during DMD treatment years after switching to a different DMD, and in post-DMD treatment years. Again, this evidence for DMD effectiveness as a class complements RCT efficacy evidence for particular DMDs. Dr. Trojano's editorial asked the question, "Is it time to recognize the use of observational data to estimate treatment effectiveness in MS?" We believe the answer is "yes." [3] Reference 3. Trojano M. Is it time to use observational data to estimate treatment effectiveness in multiple sclerosis? Neurology 2007;69:1478-1479. Disclosure: The authors report no conflicts of interest.