558678
research-article2014
MSJ0010.1177/1352458514558678Multiple Sclerosis JournalD Dahdaleh and B Sharrack
MULTIPLE SCLEROSIS MSJ JOURNAL
Controversies in MS
We can compare the relative efficacy of multiple sclerosis medications by examining the results of independent clinical trials: Yes
Multiple Sclerosis Journal 1–3 DOI: 10.1177/ 1352458514558678 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Dima Dahdaleh and Basil Sharrack
The treatment of patients with Multiple Sclerosis (MS) has been transformed over the past two decades with a rapidly expanding list of disease-modifying therapies totalling 10 in the USA and 11 elsewhere. This has made choosing a treatment more challenging for specialists and patients alike. Although direct head-to-head randomised controlled trials of all available therapeutic options would theoretically provide the best evidence base to guide patient management, we argue that this approach is impractical and fraught with difficulties; with the right tools, independent clinical trials can be used to compare the relative efficacy of treatments. Although patients with MS are heterogeneous, presenting with a wide variety of clinical manifestations and variable degrees of disease activity and progression, there are standardised criteria to establish the diagnosis and the clinical course of the illness, and to monitor its progression. Clinical trials almost universally use the McDonald’s Criteria1 to confirm the diagnosis, the Lublin criteria2 to define the clinical course, the Expanded Disability Status Scale3 to assess clinical disability and standardised magnetic resonance imaging (MRI) imaging techniques4 to monitor disease activity and progression. This makes the patient populations studied and the outcomes used reasonably comparable. In addition, although the study design of various trials may vary from one study to the other, similar outcome measures, including relapse rates, disability progression and lesion load on imaging, are invariably reported. It is therefore possible, with the use of appropriate statistical analytical tools, to use independent trials to compare treatment efficacy. There is a paucity of head-to-head treatment efficacy trials in MS. Those that have been conducted have created controversy rather than bring clarity. The
INCOMIN trial,5 which compared the efficacy of interferon beta-1b (Betaseron) with intramuscular interferon beta-1a (Avonex) in relapsing–remitting MS, showed a significant difference in the percentage of those remaining relapse free in the interferon beta-1b group. A subsequent trial6 by a Danish group published 4 years later comparing Betaseron with another interferon beta-1a (Rebif) showed no significant difference in the annual relapse rates between the two groups. A further head-to-head study comparing Rebif and Avonex, the EVIDENCE trial,7 showed that a higher percentage of patients receiving Rebif were relapse free and had fewer active lesions on MRI at 24 and 48 weeks than those on Avonex. However, there were several criticisms of this trial including the fact that it was not double-blinded and that patients were only followed up for 6 months. More recently, alemtuzumab was compared with Rebif in two phase III trials which seem to give similar results in relation to the effect of this agent on relapse rate, but different results in relation to its effect on disability progression.8,9
Correspondence to: Basil Sharrack Department of Neurology, Royal Hallamshire Hospital, Glossop Road, Sheffield S11 9BJ, UK. [email protected] Dima Dahdaleh Academic Department of Neurology, Sheffield Teaching Hospital Hospitals NHS Foundation Trust, University of Sheffield, Sheffield, UK Basil Sharrack Department of Neurology, Royal Hallamshire Hospital, Sheffield UK
These examples, and many others, highlight several issues which need to be considered. Head-to-head trials have many limitations and may not provide a definitive answer. The number of therapeutic options is rapidly expanding, and to conduct trials that would provide definitive answers requires a large number of patients taking part in a single trial with multiple therapeutic arms or a significant number of smaller trials comparing various treatment options. This is an exceptionally difficult task which requires substantial funds and the ability to follow patients up for a long period of time. Furthermore it is extremely expensive to develop new medications and conduct clinical trials. At present,
http://msj.sagepub.com 1
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Multiple Sclerosis Journal especially in the current financial climate, no government or academic institution can fulfil this need. The neurology community remains highly dependent on the pharmaceutical industry for this. It is reported that Pharmaceutical Research and Manufacturers of America member companies have spent approximately £330 billion since 2000, which they invested in research and development including clinical trials;10 the bulk of these trials were placebo controlled. Shifting the paradigm towards head-to-head trials risks disengaging pharmaceutical companies from investing in new treatments and diverting resources to smaller inconclusive studies, covering only a small proportion of potential head-to-head permutations. Network meta-analysis, which combines evidence from direct and indirect comparisons of treatments, is a well-established method that is widely accepted and used for this purpose, including the Cochrane Collaboration,11 when producing guidance for physicians. Using this approach and on the basis of the effectiveness data of several placebo-controlled trials, fingolimod was compared with interferon, glatiramer acetate and natalizumab and found to offer the most favourable profile in terms of relapse-free rate at the 1-year follow-up assessment.12 Whilst trials are relied on to guide choice of diseasemodifying treatment, patients who need such therapies may be significantly different to those included in the trials. Registries of patients with MS will prove invaluable in addressing this issue. Although several MS patient registries exist, the data collected for their databases lacks consistency at present.13 Setting up more registries and reaching a consensus to ensure uniformity of the data recorded worldwide may prove to be an invaluable resource for determining the true efficacy of treatments both in the short and long term, and for monitoring for adverse effects. Using a similar approach, the Risk-Sharing Scheme was established in the UK to assess the cost-effectiveness of first-line disease-modifying therapies by prospectively collecting disability-related data from treated patients and comparing the findings with a natural history cohort.14 In conclusion, given the robust, widely used criteria for diagnosis, grading and measuring outcomes and the relatively large number of therapeutic options, the limited resources are best spent on well-conducted robust independent trials for therapeutic drugs in MS which can, with the right statistical tools, be compared to guide clinical decision making.
Conflict of interest BS has been an investigator in clinical trials referred to in this article and has received research support paid to his institution from Biogen Idec and Merck Serono. DD declares no conflict of interest.
References 1. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292–302. 2. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014; 83: 278–286. 3. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An Expanded Disability Status Scale (EDSS). Neurology 1983; 33: 1444–1452. 4. Vrenken H, Jenkinson M, Horsfield MA, et al. Recommendations to improve imaging and analysis of brain lesion load and atrophy in longitudinal studies of multiple sclerosis. J Neurol 2013; 260: 2458–2471. 5. Durelli L, Verdun E, Barbero P, et al. Everyother-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: Results of a 2 year prospective randomized multicentre study (INCOMIN). Lancet 2002; 359: 1453–1460. 6. Koch-Henriksen N, Sorensen PS, Christensen T, et al. A randomised study of two interferon-beta treatments in relapsing-remitting multiple sclerosis. Neurology 2006; 66: 1056–1060. 7. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon β-1a treatment regimens in MS. The EVIDENCE Trial. Neurology 2002; 59: 1496–1506. 8. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet 2012; 380: 1819–1828. 9. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet 2012; 380: 1829–1839. 10. Castellani J. Head to head; are clinical trial data shared sufficiently today? Yes. BMJ 2013; 347: f1881. 11. Filippini G, Del Giovane C, Vacchi L, et al. Immunomodulators and immunosuppressants for
2 http://msj.sagepub.com
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D Dahdaleh and B Sharrack multiple sclerosis: Network meta-analysis. Cochrane Database Syst Rev 2013; 6: CD008933. 12. Del Santo F, Maratea D, Fadda V, et al. Treatments for relapsing-remitting multiple sclerosis: Summarising current information by network meta-analysis. Eur J Clin Pharmacol 2012; 68: 441–448.
13. Hurwitz BJ. Registry studies of long-term multiple sclerosis outcomes: Description of key registries. Neurology 2011; 76(Suppl 1): S3–S6. 14. Palace J, Bregenzer T, Tremlett H, et al. UK multiple sclerosis risk-sharing scheme: A new natural history dataset and an improved Markov model. BMJ Open 2014; 4: e004073.
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research-article2014
MSJ0010.1177/1352458514558678Multiple Sclerosis JournalD Dahdaleh and B Sharrack
MULTIPLE SCLEROSIS MSJ JOURNAL
Controversies in MS
We can compare the relative efficacy of multiple sclerosis medications by examining the results of independent clinical trials: Yes
Multiple Sclerosis Journal 1–3 DOI: 10.1177/ 1352458514558678 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Dima Dahdaleh and Basil Sharrack
The treatment of patients with Multiple Sclerosis (MS) has been transformed over the past two decades with a rapidly expanding list of disease-modifying therapies totalling 10 in the USA and 11 elsewhere. This has made choosing a treatment more challenging for specialists and patients alike. Although direct head-to-head randomised controlled trials of all available therapeutic options would theoretically provide the best evidence base to guide patient management, we argue that this approach is impractical and fraught with difficulties; with the right tools, independent clinical trials can be used to compare the relative efficacy of treatments. Although patients with MS are heterogeneous, presenting with a wide variety of clinical manifestations and variable degrees of disease activity and progression, there are standardised criteria to establish the diagnosis and the clinical course of the illness, and to monitor its progression. Clinical trials almost universally use the McDonald’s Criteria1 to confirm the diagnosis, the Lublin criteria2 to define the clinical course, the Expanded Disability Status Scale3 to assess clinical disability and standardised magnetic resonance imaging (MRI) imaging techniques4 to monitor disease activity and progression. This makes the patient populations studied and the outcomes used reasonably comparable. In addition, although the study design of various trials may vary from one study to the other, similar outcome measures, including relapse rates, disability progression and lesion load on imaging, are invariably reported. It is therefore possible, with the use of appropriate statistical analytical tools, to use independent trials to compare treatment efficacy. There is a paucity of head-to-head treatment efficacy trials in MS. Those that have been conducted have created controversy rather than bring clarity. The
INCOMIN trial,5 which compared the efficacy of interferon beta-1b (Betaseron) with intramuscular interferon beta-1a (Avonex) in relapsing–remitting MS, showed a significant difference in the percentage of those remaining relapse free in the interferon beta-1b group. A subsequent trial6 by a Danish group published 4 years later comparing Betaseron with another interferon beta-1a (Rebif) showed no significant difference in the annual relapse rates between the two groups. A further head-to-head study comparing Rebif and Avonex, the EVIDENCE trial,7 showed that a higher percentage of patients receiving Rebif were relapse free and had fewer active lesions on MRI at 24 and 48 weeks than those on Avonex. However, there were several criticisms of this trial including the fact that it was not double-blinded and that patients were only followed up for 6 months. More recently, alemtuzumab was compared with Rebif in two phase III trials which seem to give similar results in relation to the effect of this agent on relapse rate, but different results in relation to its effect on disability progression.8,9
Correspondence to: Basil Sharrack Department of Neurology, Royal Hallamshire Hospital, Glossop Road, Sheffield S11 9BJ, UK. [email protected] Dima Dahdaleh Academic Department of Neurology, Sheffield Teaching Hospital Hospitals NHS Foundation Trust, University of Sheffield, Sheffield, UK Basil Sharrack Department of Neurology, Royal Hallamshire Hospital, Sheffield UK
These examples, and many others, highlight several issues which need to be considered. Head-to-head trials have many limitations and may not provide a definitive answer. The number of therapeutic options is rapidly expanding, and to conduct trials that would provide definitive answers requires a large number of patients taking part in a single trial with multiple therapeutic arms or a significant number of smaller trials comparing various treatment options. This is an exceptionally difficult task which requires substantial funds and the ability to follow patients up for a long period of time. Furthermore it is extremely expensive to develop new medications and conduct clinical trials. At present,
http://msj.sagepub.com 1
Downloaded from msj.sagepub.com at UNIV OF PITTSBURGH on January 11, 2015
Multiple Sclerosis Journal especially in the current financial climate, no government or academic institution can fulfil this need. The neurology community remains highly dependent on the pharmaceutical industry for this. It is reported that Pharmaceutical Research and Manufacturers of America member companies have spent approximately £330 billion since 2000, which they invested in research and development including clinical trials;10 the bulk of these trials were placebo controlled. Shifting the paradigm towards head-to-head trials risks disengaging pharmaceutical companies from investing in new treatments and diverting resources to smaller inconclusive studies, covering only a small proportion of potential head-to-head permutations. Network meta-analysis, which combines evidence from direct and indirect comparisons of treatments, is a well-established method that is widely accepted and used for this purpose, including the Cochrane Collaboration,11 when producing guidance for physicians. Using this approach and on the basis of the effectiveness data of several placebo-controlled trials, fingolimod was compared with interferon, glatiramer acetate and natalizumab and found to offer the most favourable profile in terms of relapse-free rate at the 1-year follow-up assessment.12 Whilst trials are relied on to guide choice of diseasemodifying treatment, patients who need such therapies may be significantly different to those included in the trials. Registries of patients with MS will prove invaluable in addressing this issue. Although several MS patient registries exist, the data collected for their databases lacks consistency at present.13 Setting up more registries and reaching a consensus to ensure uniformity of the data recorded worldwide may prove to be an invaluable resource for determining the true efficacy of treatments both in the short and long term, and for monitoring for adverse effects. Using a similar approach, the Risk-Sharing Scheme was established in the UK to assess the cost-effectiveness of first-line disease-modifying therapies by prospectively collecting disability-related data from treated patients and comparing the findings with a natural history cohort.14 In conclusion, given the robust, widely used criteria for diagnosis, grading and measuring outcomes and the relatively large number of therapeutic options, the limited resources are best spent on well-conducted robust independent trials for therapeutic drugs in MS which can, with the right statistical tools, be compared to guide clinical decision making.
Conflict of interest BS has been an investigator in clinical trials referred to in this article and has received research support paid to his institution from Biogen Idec and Merck Serono. DD declares no conflict of interest.
References 1. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292–302. 2. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014; 83: 278–286. 3. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An Expanded Disability Status Scale (EDSS). Neurology 1983; 33: 1444–1452. 4. Vrenken H, Jenkinson M, Horsfield MA, et al. Recommendations to improve imaging and analysis of brain lesion load and atrophy in longitudinal studies of multiple sclerosis. J Neurol 2013; 260: 2458–2471. 5. Durelli L, Verdun E, Barbero P, et al. Everyother-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: Results of a 2 year prospective randomized multicentre study (INCOMIN). Lancet 2002; 359: 1453–1460. 6. Koch-Henriksen N, Sorensen PS, Christensen T, et al. A randomised study of two interferon-beta treatments in relapsing-remitting multiple sclerosis. Neurology 2006; 66: 1056–1060. 7. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon β-1a treatment regimens in MS. The EVIDENCE Trial. Neurology 2002; 59: 1496–1506. 8. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet 2012; 380: 1819–1828. 9. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet 2012; 380: 1829–1839. 10. Castellani J. Head to head; are clinical trial data shared sufficiently today? Yes. BMJ 2013; 347: f1881. 11. Filippini G, Del Giovane C, Vacchi L, et al. Immunomodulators and immunosuppressants for
2 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV OF PITTSBURGH on January 11, 2015
D Dahdaleh and B Sharrack multiple sclerosis: Network meta-analysis. Cochrane Database Syst Rev 2013; 6: CD008933. 12. Del Santo F, Maratea D, Fadda V, et al. Treatments for relapsing-remitting multiple sclerosis: Summarising current information by network meta-analysis. Eur J Clin Pharmacol 2012; 68: 441–448.
13. Hurwitz BJ. Registry studies of long-term multiple sclerosis outcomes: Description of key registries. Neurology 2011; 76(Suppl 1): S3–S6. 14. Palace J, Bregenzer T, Tremlett H, et al. UK multiple sclerosis risk-sharing scheme: A new natural history dataset and an improved Markov model. BMJ Open 2014; 4: e004073.
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
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