579446
research-article2015
MSJ0010.1177/1352458515579446Multiple Sclerosis JournalJ Palace
MULTIPLE SCLEROSIS MSJ JOURNAL
Controversies in multiple sclerosis
Placebo studies should not be undertaken in NMO – Yes
Multiple Sclerosis Journal 2015, Vol. 21(6) 689–691 DOI: 10.1177/ 1352458515579446 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Jacqueline Palace
Neuromyelitis optica and its spectrum (NMOSD) are now recognized as being antibody-mediated conditions of the central nervous system. The antibodies are directed against aquaporin 4 water channels located on astrocyte foot processes, and their presence in the serum is associated with a relapsing phenotype.1,2 NMOSD has a predilection for the optic nerves and spinal cord and is associated with a high morbidity and mortality. Disability is solely relapse related (in contrast to MS where disability is mainly accrued during the progressive phase) and many patients are left severely visually impaired or paraplegic, even after one attack.3 Even prior to the discovery of the antibodies, when the disease was thought to be a variant of MS, patients were noted to be responsive to, and often treated with, immunosuppression.4,5 Since the recognition of the pathogenic antibodies, it has become standard of care to treat all AQP4 antibody positive patients with immunotherapy, and most physicians would also treat sero-negative patients if they have a relapsing course. The recent emergence of clinical trials in NMO has led to lively discussion around the design, with the US Food and Drug Administration requiring placebo controlled studies, whereas the European Medicines Agency supports non-placebo designs in order to ensure all patients have access to the current ‘standard of care’. This author does not support ‘placebo only’ arms in clinical trials due to the concern of placing individual patients at increased risk of relapse and permanent disability. Current treatment: studies and clinical practice Treatments of other antibody mediated diseases It is well accepted in other antibody-mediated diseases that immunosuppressive therapy is beneficial, and thus standard therapy for conditions such as myasthenia gravis includes corticosteroids, azathioprine,
methotrexate and mycophenolate mofetil. Other diseases, such as the auto-antibody encephalopathies are treated similarly and it seems unnecessary (scientifically and for clinical risk reasons) to reinvent the wheel by performing randomized controlled trials each time a new auto-antibody is identified. Indeed similar immunosuppressive regimes are used to prevent rejection after solid organ transplantation.
Correspondence to: Jacqueline Palace Neurology Department, University of Oxford and Oxford Radcliffe Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK. jacqueline.palace@ndcn. ox.ac.uk
Consensus guidelines The general principles of treating antibody mediated conditions similarly, clinicians’ direct experience, and observational studies supporting a response of NMO patients to immunosuppressive therapies have led to the current standard of care. This is to treat all AQP4 antibody patients with immunosuppressive or immunomodulatory therapy, and is reflected in the European Federation of Neurological Societies’ guidelines6 and the consensus document produced by an international group of NMO experts7. Observational studies In this rare condition, the scientific support for immunosuppression is based upon observational studies, (because randomized controlled trials have not been performed), and the outcomes have focused on before treatment relapse activity. Indeed all publications report a reduction of relapse rates with immunosuppressive therapies, which contrasts with a worsening or no response when treated with the MS drug betainterferon. Additionally, an acute relapse response to corticosteroids and plasma exchange in severe cases is now universally accepted. The earlier diagnosis and treatment of NMO that has resulted from the discovery of AQP4 antibodies has mirrored a reduction in the mortality rate over the past 20 years.8 A recent report also suggests that relapses, when they do occur, may recover better when patients are on immunosuppressive treatment9.
http://msj.sagepub.com 689
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
Multiple Sclerosis Journal 21(6) NMO study design Designing studies that answer relevant questions The currently accepted treatment regimes are generally cheap with well established safety profiles, and therefore it is important to assess how new and more expensive treatments with less safety data, compare. A placebo-controlled trial of new therapies against no treatment will not answer the question ‘are these new treatments better and safer than current treatments’. In countries where cost-effectiveness is part of health care commissioning decisions, a placebo study may lead to licensing of a drug that will not be funded by the state until proven to be better than current therapies. Setting up a trial design which is likely to succeed A placebo study is not likely to be easy to recruit to. Patients will have had their onset relapse while off treatment, and due to delays in diagnosis, often a number of further relapses prior to immunosuppression. They will then have been advised to take immunosuppressive therapy to reduce the risk of further relapses. A placebo study will require patients to be asked to take the risk of withdrawing previously strongly-recommended treatment, and there is a real chance that there will be under-recruitment to the study. In addition there are likely to be recruitment biases, favouring selection of patients with milder disease (when the doctor may feel the risk of placebo is less) or selection of patients with drug resistant disease when all standard therapies have already failed so there is ‘less to lose’, and both these biases may lead to an underpowered study. Powering a study is easier with a placebo study Supporters of placebo studies have highlighted that the total number of relapses required to show a statistically significant difference between the active treatment and the placebo is less than when comparing active to current treatment. However, this only applies if current immunosuppressive treatments work; this is challenged by those supporting placebo arms. Collecting safety data Due to concern about subjecting a patient to greater risk in a placebo study, the designs, as currently proposed, aim to reduce the risk by shortening the time in the comparative stage. In addition, time to relapse (which is the primary NMO outcome, because
relapses can be associated with permanent disability) are likely to be shorter on placebo than on standard immunotherapy, and this will lead to earlier escape from the randomized placebo phase of the study. Thus, a placebo study will have a shorter comparative stage, and thus less comparative safety data on the new treatment will be gathered. Ethical considerations Commercial interests Setting up a study in a rare condition is challenging, and using a placebo arm will make it easier to show a treatment effect in the active arm. Thus, there will be commercial advantages in supporting this design. Pressure on clinicians to ‘sell’ a placebo study Because all NMO experts currently recommend immunosuppressive treatments to patients with AQP4 antibody disease it will be difficult for these experts to recruit for a placebo study without an alteration of advice to patients. This may lead to subtle pressures on clinicians to change how they discuss current therapies in order to be able to achieve their recruitment targets. Less harm to the whole patient group versus greater risk to an individual patient In addition to inferring that current therapies must be efficacious if a placebo comparative design requires fewer total relapses to show efficacy, the idea that having fewer total relapses is more ethical, even if an individual patient is at higher risk of relapse, is flawed. This is analogous to saying a study of chemotherapy in breast cancer should be performed against nothing because one can show the treatment works more easily (i.e. fewer total deaths) even though each individual patient is at greater risk of death. Summary In summary, there are many reasons for comparing new treatments against currently used therapies. These include the widespread acceptance of current immunotherapies, the reduction of harm to individual patients, design of trials that answer relevant questions in clinical practice and ethical concerns. Conflict of interest Jacqueline Palace is partly funded by highly specialized services to run a national congenital myasthenia service and a neuromyelitis service. She has received
690 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
BM Greenberg support for scientific meetings and honorariums for advisory work from Merck Serono, Biogen Idec, Novartis, Teva, Chugai Pharma, Alexion and Bayer Schering, and unrestricted grants from Merck Serono, Novartis, Biogen Idec and Bayer Schering and Teva. Her hospital trust receives funds for her role as clinical lead for the RSS, and she has received grants from the MS society and Guthie Jackson Foundation for unrelated research studies. She is a board member for the charitable European MS foundation ‘The Charcot Foundation’ and on the steering committee for a European collaborative MS imaging group ‘MAGNIMS’. Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
References 1. Weinshenker B, Wingerchuk D, Vukusic S, et al. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Ann Neurol 2006; 59: 566–569. 2.
Matiello M, Lennon V, Jacob A, et al. NMO-IgG predicts the outcome of recurrent optic neuritis. Neurology 2008; 70: 2197–2200.
3. Kitley J, Leite MI, Nakashima I, et al. Prognostic factors and disease course in aquaporin-4 antibodypositive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain 2012; 135: 1834–1849. 4. Mandler RN, Ahmed W, Dencoff JE. Devic’s neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology 1998; 51: 1219–1220. 5. Wingerchuk D, Hogancamp W, O’Brien P, et al. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology 1999; 53: 1107–1114. 6.
Sellner J, Boggild M, Clanet M, et al. EFNS guidelines on diagnosis and management of neuromyelitis optica. Euro J Neurol 2010; 17: 1019–1032.
7.
Kimbrough DJ, Fujihara K, Jacob A, et al. Treatment of neuromyelitis optica: Review and recommendations. Mult Scler Rel Dis 2012; 1: 180–187.
8. EMA Regulatory Workshop on Clinical Trials Designs in Neuromyelitis Optica (NMO) and Spectrum Disorders Oct 2014: Current Standard of Care - clinical view. Romain Marignier http:// www.ema.europa.eu/docs/en_GB/document_library/ Presentation/2014/10/WC500176305.pdf 9.
Tackley G, O’Brien F, Leite MI, et al. Neuromyelitis optica: annual relapse rates off and on immunosuppression and the relationship to attack type and ethnicity. Mult Scler J 2014; 20(suppl 1): 352
Placebo studies should not be undertaken in NMO – No
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
Multiple Sclerosis Journal 2015, Vol. 21(6) 691–693 DOI: 10.1177/ 1352458515579217 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Benjamin M Greenberg, MD, MHS
Therapeutic trials in rare diseases have a number of challenges beyond sample size limitations. Yet, the presence of these challenges does not obfuscate the obligation of clinicians to acquire valid data relative to therapies. Making large scale recommendations for potentially dangerous therapies is appropriate when mechanisms for obtaining appropriate evidence are impossible. In the neuromyelitis optica (NMO) community, we have found ourselves at a crossroads relative to clinical trials, igniting significant debate about the ethics surrounding placebo-controlled trial design. Those who argue against the need for such trials or even suggest that they are unethical have fallen victim to medicine’s most dangerous nemesis – dogma established through experience.
There are three fallacies that have been used to dispute the need for placebo-controlled trials in NMO. The first and most important is the argument that there is ample evidence to prove currently prescribed therapies (i.e. Rituximab, mycophenolate mofetil, azathioprine, corticosteroids) are effective treatments. The basis for this proclamation comes from the experience of seasoned NMO clinicians, open label trials and retrospective studies.1 This data is extracted from studies falling in the lowest category of evidence which are all subject to extreme biases and faulty conclusions. The history of medicine is rife with examples of clinical scenarios where there existed ‘overwhelming evidence’ of therapeutic benefit from an intervention based on experience, open label studies and
Correspondence to: Benjamin Greenberg Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA Benjamin.Greenberg@ UTSouthwestern.edu
http://msj.sagepub.com 691
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
research-article2015
MSJ0010.1177/1352458515579446Multiple Sclerosis JournalJ Palace
MULTIPLE SCLEROSIS MSJ JOURNAL
Controversies in multiple sclerosis
Placebo studies should not be undertaken in NMO – Yes
Multiple Sclerosis Journal 2015, Vol. 21(6) 689–691 DOI: 10.1177/ 1352458515579446 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Jacqueline Palace
Neuromyelitis optica and its spectrum (NMOSD) are now recognized as being antibody-mediated conditions of the central nervous system. The antibodies are directed against aquaporin 4 water channels located on astrocyte foot processes, and their presence in the serum is associated with a relapsing phenotype.1,2 NMOSD has a predilection for the optic nerves and spinal cord and is associated with a high morbidity and mortality. Disability is solely relapse related (in contrast to MS where disability is mainly accrued during the progressive phase) and many patients are left severely visually impaired or paraplegic, even after one attack.3 Even prior to the discovery of the antibodies, when the disease was thought to be a variant of MS, patients were noted to be responsive to, and often treated with, immunosuppression.4,5 Since the recognition of the pathogenic antibodies, it has become standard of care to treat all AQP4 antibody positive patients with immunotherapy, and most physicians would also treat sero-negative patients if they have a relapsing course. The recent emergence of clinical trials in NMO has led to lively discussion around the design, with the US Food and Drug Administration requiring placebo controlled studies, whereas the European Medicines Agency supports non-placebo designs in order to ensure all patients have access to the current ‘standard of care’. This author does not support ‘placebo only’ arms in clinical trials due to the concern of placing individual patients at increased risk of relapse and permanent disability. Current treatment: studies and clinical practice Treatments of other antibody mediated diseases It is well accepted in other antibody-mediated diseases that immunosuppressive therapy is beneficial, and thus standard therapy for conditions such as myasthenia gravis includes corticosteroids, azathioprine,
methotrexate and mycophenolate mofetil. Other diseases, such as the auto-antibody encephalopathies are treated similarly and it seems unnecessary (scientifically and for clinical risk reasons) to reinvent the wheel by performing randomized controlled trials each time a new auto-antibody is identified. Indeed similar immunosuppressive regimes are used to prevent rejection after solid organ transplantation.
Correspondence to: Jacqueline Palace Neurology Department, University of Oxford and Oxford Radcliffe Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK. jacqueline.palace@ndcn. ox.ac.uk
Consensus guidelines The general principles of treating antibody mediated conditions similarly, clinicians’ direct experience, and observational studies supporting a response of NMO patients to immunosuppressive therapies have led to the current standard of care. This is to treat all AQP4 antibody patients with immunosuppressive or immunomodulatory therapy, and is reflected in the European Federation of Neurological Societies’ guidelines6 and the consensus document produced by an international group of NMO experts7. Observational studies In this rare condition, the scientific support for immunosuppression is based upon observational studies, (because randomized controlled trials have not been performed), and the outcomes have focused on before treatment relapse activity. Indeed all publications report a reduction of relapse rates with immunosuppressive therapies, which contrasts with a worsening or no response when treated with the MS drug betainterferon. Additionally, an acute relapse response to corticosteroids and plasma exchange in severe cases is now universally accepted. The earlier diagnosis and treatment of NMO that has resulted from the discovery of AQP4 antibodies has mirrored a reduction in the mortality rate over the past 20 years.8 A recent report also suggests that relapses, when they do occur, may recover better when patients are on immunosuppressive treatment9.
http://msj.sagepub.com 689
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
Multiple Sclerosis Journal 21(6) NMO study design Designing studies that answer relevant questions The currently accepted treatment regimes are generally cheap with well established safety profiles, and therefore it is important to assess how new and more expensive treatments with less safety data, compare. A placebo-controlled trial of new therapies against no treatment will not answer the question ‘are these new treatments better and safer than current treatments’. In countries where cost-effectiveness is part of health care commissioning decisions, a placebo study may lead to licensing of a drug that will not be funded by the state until proven to be better than current therapies. Setting up a trial design which is likely to succeed A placebo study is not likely to be easy to recruit to. Patients will have had their onset relapse while off treatment, and due to delays in diagnosis, often a number of further relapses prior to immunosuppression. They will then have been advised to take immunosuppressive therapy to reduce the risk of further relapses. A placebo study will require patients to be asked to take the risk of withdrawing previously strongly-recommended treatment, and there is a real chance that there will be under-recruitment to the study. In addition there are likely to be recruitment biases, favouring selection of patients with milder disease (when the doctor may feel the risk of placebo is less) or selection of patients with drug resistant disease when all standard therapies have already failed so there is ‘less to lose’, and both these biases may lead to an underpowered study. Powering a study is easier with a placebo study Supporters of placebo studies have highlighted that the total number of relapses required to show a statistically significant difference between the active treatment and the placebo is less than when comparing active to current treatment. However, this only applies if current immunosuppressive treatments work; this is challenged by those supporting placebo arms. Collecting safety data Due to concern about subjecting a patient to greater risk in a placebo study, the designs, as currently proposed, aim to reduce the risk by shortening the time in the comparative stage. In addition, time to relapse (which is the primary NMO outcome, because
relapses can be associated with permanent disability) are likely to be shorter on placebo than on standard immunotherapy, and this will lead to earlier escape from the randomized placebo phase of the study. Thus, a placebo study will have a shorter comparative stage, and thus less comparative safety data on the new treatment will be gathered. Ethical considerations Commercial interests Setting up a study in a rare condition is challenging, and using a placebo arm will make it easier to show a treatment effect in the active arm. Thus, there will be commercial advantages in supporting this design. Pressure on clinicians to ‘sell’ a placebo study Because all NMO experts currently recommend immunosuppressive treatments to patients with AQP4 antibody disease it will be difficult for these experts to recruit for a placebo study without an alteration of advice to patients. This may lead to subtle pressures on clinicians to change how they discuss current therapies in order to be able to achieve their recruitment targets. Less harm to the whole patient group versus greater risk to an individual patient In addition to inferring that current therapies must be efficacious if a placebo comparative design requires fewer total relapses to show efficacy, the idea that having fewer total relapses is more ethical, even if an individual patient is at higher risk of relapse, is flawed. This is analogous to saying a study of chemotherapy in breast cancer should be performed against nothing because one can show the treatment works more easily (i.e. fewer total deaths) even though each individual patient is at greater risk of death. Summary In summary, there are many reasons for comparing new treatments against currently used therapies. These include the widespread acceptance of current immunotherapies, the reduction of harm to individual patients, design of trials that answer relevant questions in clinical practice and ethical concerns. Conflict of interest Jacqueline Palace is partly funded by highly specialized services to run a national congenital myasthenia service and a neuromyelitis service. She has received
690 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
BM Greenberg support for scientific meetings and honorariums for advisory work from Merck Serono, Biogen Idec, Novartis, Teva, Chugai Pharma, Alexion and Bayer Schering, and unrestricted grants from Merck Serono, Novartis, Biogen Idec and Bayer Schering and Teva. Her hospital trust receives funds for her role as clinical lead for the RSS, and she has received grants from the MS society and Guthie Jackson Foundation for unrelated research studies. She is a board member for the charitable European MS foundation ‘The Charcot Foundation’ and on the steering committee for a European collaborative MS imaging group ‘MAGNIMS’. Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
References 1. Weinshenker B, Wingerchuk D, Vukusic S, et al. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Ann Neurol 2006; 59: 566–569. 2.
Matiello M, Lennon V, Jacob A, et al. NMO-IgG predicts the outcome of recurrent optic neuritis. Neurology 2008; 70: 2197–2200.
3. Kitley J, Leite MI, Nakashima I, et al. Prognostic factors and disease course in aquaporin-4 antibodypositive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain 2012; 135: 1834–1849. 4. Mandler RN, Ahmed W, Dencoff JE. Devic’s neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology 1998; 51: 1219–1220. 5. Wingerchuk D, Hogancamp W, O’Brien P, et al. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology 1999; 53: 1107–1114. 6.
Sellner J, Boggild M, Clanet M, et al. EFNS guidelines on diagnosis and management of neuromyelitis optica. Euro J Neurol 2010; 17: 1019–1032.
7.
Kimbrough DJ, Fujihara K, Jacob A, et al. Treatment of neuromyelitis optica: Review and recommendations. Mult Scler Rel Dis 2012; 1: 180–187.
8. EMA Regulatory Workshop on Clinical Trials Designs in Neuromyelitis Optica (NMO) and Spectrum Disorders Oct 2014: Current Standard of Care - clinical view. Romain Marignier http:// www.ema.europa.eu/docs/en_GB/document_library/ Presentation/2014/10/WC500176305.pdf 9.
Tackley G, O’Brien F, Leite MI, et al. Neuromyelitis optica: annual relapse rates off and on immunosuppression and the relationship to attack type and ethnicity. Mult Scler J 2014; 20(suppl 1): 352
Placebo studies should not be undertaken in NMO – No
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
Multiple Sclerosis Journal 2015, Vol. 21(6) 691–693 DOI: 10.1177/ 1352458515579217 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Benjamin M Greenberg, MD, MHS
Therapeutic trials in rare diseases have a number of challenges beyond sample size limitations. Yet, the presence of these challenges does not obfuscate the obligation of clinicians to acquire valid data relative to therapies. Making large scale recommendations for potentially dangerous therapies is appropriate when mechanisms for obtaining appropriate evidence are impossible. In the neuromyelitis optica (NMO) community, we have found ourselves at a crossroads relative to clinical trials, igniting significant debate about the ethics surrounding placebo-controlled trial design. Those who argue against the need for such trials or even suggest that they are unethical have fallen victim to medicine’s most dangerous nemesis – dogma established through experience.
There are three fallacies that have been used to dispute the need for placebo-controlled trials in NMO. The first and most important is the argument that there is ample evidence to prove currently prescribed therapies (i.e. Rituximab, mycophenolate mofetil, azathioprine, corticosteroids) are effective treatments. The basis for this proclamation comes from the experience of seasoned NMO clinicians, open label trials and retrospective studies.1 This data is extracted from studies falling in the lowest category of evidence which are all subject to extreme biases and faulty conclusions. The history of medicine is rife with examples of clinical scenarios where there existed ‘overwhelming evidence’ of therapeutic benefit from an intervention based on experience, open label studies and
Correspondence to: Benjamin Greenberg Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA Benjamin.Greenberg@ UTSouthwestern.edu
http://msj.sagepub.com 691
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
