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
Multiple Sclerosis Journal 21(6) retrospective studies, followed by discovery that the intervention was not helpful, or even harmful, when studied in controlled trials. In open label studies and animal models of amyotrophic lateral sclerosis (ALS), for example, data suggested a therapeutic benefit of minocycline. When well designed, placebo-controlled trials were suggested, many patients and clinicians decried them as unethical. Minocycline was a ‘benign’ drug and ALS patients were dying. Anything that could slow the progression should be used. In the end, a phase three trial was completed and minocycline was found to hasten the death of the patients who clinicians were trying to help. Sometimes it is good to be in the placebo arm of a trial.2 This is just one example, but there are many dogmas established by limited evidence that have proven false in clinical trials (e.g. renal dosed dopamine, prophylactic antiepileptic drugs post intracerebral hemorrhage, etc.); yet, clinicians continue to fail in their obligation to treat recommendations with scepticism.3 Clinicians frequently discount the potential of their well-intentioned, appropriate empiric therapies to cause harm. Empiric treatment in the absence of data is warranted and, indeed, is the duty of a physician, but data derived from empiricism should never be used as a substitute for an appropriately designed trial to answer important questions for the many generations of patients who will be following our advice. The second dogma in NMO that should be challenged is the view that the risks associated with NMO are too great. The presumption is that all, or even most, exacerbations of NMO lead to irreversible disability. While NMO has the definite potential to cause severe life-altering, or even life-threatening, exacerbations, the rates of these events are far less than originally described. There are two very important reasons for this. First, acute interventions (e.g. corticosteroids and plasma exchange) seem to lessen the residual deficits of attacks (although this too needs to be proven). Second, the number and types of patients being diagnosed with NMO are very different from a decade ago. With the widespread availability and use of the anti-AQP4 assay, clinicians are treating a large number of patients with immunosuppressive therapies that would have never been recognized as NMO when outcomes data were first presented. The original descriptions of outcome came from a time when NMO patients were identified based on their extreme phenotype that differentiated them from MS. Thus, their very ability to be diagnosed was based on having a severe phenotype. The currently diagnosed group of patients has a broader array of phenotypes. In this scenario, risk–benefit calculations are more difficult. There are documented cases of NMO patients going
many years without therapy and having no attacks. Neurologists currently advocate treating all NMO patients with immunosuppression, but we should we are potentially over-treating. I, like my colleagues, am doing the best I can with limited data. Yet, it is precisely because of the limitations of the data that I support well-designed placebo-controlled therapeutic trials. The third dogma pronounced by those who argue against placebo-controlled trials is that we are experimenting on our patients and not protecting them. In many meetings I have heard a clinician state that our first duty is ‘primum non nocere’ (first do no harm). This Latin phrase is commonly misattributed to the Hippocratic oath – in which it does not appear.4 Beyond the mistakes made relating to its origin, clinicians use this phrase in fallacious inflammatory ways in an attempt to shame adversaries into believing they are behaving in an unethical fashion. One could easily turn this argument around and suggest that putting patients on unproven, lifelong immunosuppression in the hope it reduces the risk of a relapse is potentially doing harm. Since azathioprine has a higher rate of lymphoma than mycophenolate mofetil, are my colleagues who prefer azathioprine for NMO breaking a sacred oath? No. Primum non nocere is an important guiding force for physicians, but sometimes it is hard to define what is the most harmful. Is pursuing well-designed placebo-controlled trials with full informed consent, options to leave the trial and a data safety monitoring board more harmful that recommending lifelong immunosuppression to a 20-year-old based on our collective experience? Finally, it is worth noting that our current experience with agents for NMO are completely devoid of the most critical piece of data – safety. Even if the efficacy data was reliable (which it isn’t), none of our retrospective studies have adequately quantified safety. There were no systematic measures of adverse events, serious adverse events, infections or deaths secondary to treatment. How can we defend our empirical data as adequate enough to forego placebocontrolled trials when we might be causing harm in excess of benefit? It is possible that a head-to-head trial of experimental drug X would appear superior to an active comparator and gain approval, but in reality it could be no better than placebo. That outcome would not be fulfilling our obligation to do no harm. On the contrary, we would be perpetuating a dogma that could cause harm for many generations of patients. For all of these reasons, placebo-controlled trials are needed and ethical in NMO.
692 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
BG Weinshenker Dr Greenberg has received consulting fees from Chugai, Novartis, EMD Serono and Medimmune. He has received grant support from the NIH, PCORI, Biogen and the Guthy Jackson Charitable Foundation. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. References 1. Kimbrough DJ, Fujihara K, Jacob A, et al. Treatment of neuromyelitis optica: Review and
recommendations. Mult Scler Rel Dis 2012; 1: 180–187. 2. Gordon PH, Moore DH, Miller RG, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007; 6: 1045–1053. 3. Messe SR, Sansing LH, Cucchiara BL, et al. Prophylactic antiepileptic drug use is associated with poor outcome following ICH. Neurocrit Care 2009; 11: 38–44. 4. Smith CM. Origin and uses of primum non nocere – above all, do no harm! J Clin Pharmacol 2005; 45: 371–377.57 7 MSJ0010.1177/1352458515579217Multiple Sclerosis JournalBM Greenbergresearch-article2015
Placebo Studies should not be Undertaken in Neuromyelitis Optica: Commentary
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
Multiple Sclerosis Journal 2015, Vol. 21(6) 693–694 DOI: 10.1177/ 1352458515580402 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Brian G Weinshenker
Definitive phase 3 clinical trials for neuromyelitis optica (NMO), previously unthinkable, have become feasible and have actually begun in 2014.1 This achievement has resulted because of key advances over the past 15 years, including: (1) definitive diagnosis and separation of NMO from multiple sclerosis in the majority of patients at an early point in the disease before major irreversible disability; (2) recognition of a comprehensive spectrum of disease presentations aided by a specific biomarker, aquaporin-4 IgG; (3) rational selection of treatments based on understanding of the pathogenesis of NMO. However, progress is threatened by conflicting concerns regarding the need for and the acceptability of placebo-controlled clinical trials in NMO. Regulators in different jurisdictions have provided less than consistent guidance, in part due to differing opinions expressed to them by NMO experts on the subject. Palace and Greenberg nicely summarize the issues. Palace argues that the risk of even a single attack of irreversible disability cannot be asked from a patient given current knowledge and that observational studies in NMO and in a variety of other antibodymediated diseases adequately establish a standard of therapy for NMO; “reinventing the wheel” by conducting placebo-controlled studies is unnecessary. Greenberg argues that the evidence from retrospective studies is potentially flawed, backed up by previous experience from other diseases, for which the efficacy of agents presumed to be effective was
disproven in placebo-controlled clinical trials. He contends that the expanding spectrum of NMO does not allow us to assume that the severity of attacks for contemporary NMO is adequately documented in studies of decades ago; furthermore, arguing that current therapies are a standard of treatment ignores their potential safety risks. Theoretically, newer, targeted immunotherapies, such as monoclonal antibodies, may be safer than older less specific immunosuppressive treatments, though long-term studies will be required to establish the safety even of specific agents. Unexpectedly high frequency of certain infections2 and paradoxical autoimmunity3 have been observed with MS monoclonal antibody treatments.
Correspondence to: Brian G Weinshenker Professor of Neurology, Mayo Clinic, 200 First Street SW Rochester, MN 55905, USA. [email protected] Brian G Weinshenker Mayo Clinic, Rochester, USA
The arguments on both sides are meritorious. But what is the path forward? As one who previously espoused Palace’s arguments but has been convinced that placebo-controlled studies for NMO are acceptable under certain circumstances, I was most swayed by the fundamental principle that placebo-controlled trials are the standard for scientific rigor and having such an evidence base at an early point in therapeutic development for a disease is worthwhile. Treatments such as thymectomy for non-thymoma myasthenia gravis have been performed for decades despite no definitive study and continuing controversy about its efficacy.4 Although a clinical trial has been started years after being considered a standard of practice in many centers.5 enrollment has been difficult and did not meet targets. We may
http://msj.sagepub.com 693
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
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
Multiple Sclerosis Journal 21(6) retrospective studies, followed by discovery that the intervention was not helpful, or even harmful, when studied in controlled trials. In open label studies and animal models of amyotrophic lateral sclerosis (ALS), for example, data suggested a therapeutic benefit of minocycline. When well designed, placebo-controlled trials were suggested, many patients and clinicians decried them as unethical. Minocycline was a ‘benign’ drug and ALS patients were dying. Anything that could slow the progression should be used. In the end, a phase three trial was completed and minocycline was found to hasten the death of the patients who clinicians were trying to help. Sometimes it is good to be in the placebo arm of a trial.2 This is just one example, but there are many dogmas established by limited evidence that have proven false in clinical trials (e.g. renal dosed dopamine, prophylactic antiepileptic drugs post intracerebral hemorrhage, etc.); yet, clinicians continue to fail in their obligation to treat recommendations with scepticism.3 Clinicians frequently discount the potential of their well-intentioned, appropriate empiric therapies to cause harm. Empiric treatment in the absence of data is warranted and, indeed, is the duty of a physician, but data derived from empiricism should never be used as a substitute for an appropriately designed trial to answer important questions for the many generations of patients who will be following our advice. The second dogma in NMO that should be challenged is the view that the risks associated with NMO are too great. The presumption is that all, or even most, exacerbations of NMO lead to irreversible disability. While NMO has the definite potential to cause severe life-altering, or even life-threatening, exacerbations, the rates of these events are far less than originally described. There are two very important reasons for this. First, acute interventions (e.g. corticosteroids and plasma exchange) seem to lessen the residual deficits of attacks (although this too needs to be proven). Second, the number and types of patients being diagnosed with NMO are very different from a decade ago. With the widespread availability and use of the anti-AQP4 assay, clinicians are treating a large number of patients with immunosuppressive therapies that would have never been recognized as NMO when outcomes data were first presented. The original descriptions of outcome came from a time when NMO patients were identified based on their extreme phenotype that differentiated them from MS. Thus, their very ability to be diagnosed was based on having a severe phenotype. The currently diagnosed group of patients has a broader array of phenotypes. In this scenario, risk–benefit calculations are more difficult. There are documented cases of NMO patients going
many years without therapy and having no attacks. Neurologists currently advocate treating all NMO patients with immunosuppression, but we should we are potentially over-treating. I, like my colleagues, am doing the best I can with limited data. Yet, it is precisely because of the limitations of the data that I support well-designed placebo-controlled therapeutic trials. The third dogma pronounced by those who argue against placebo-controlled trials is that we are experimenting on our patients and not protecting them. In many meetings I have heard a clinician state that our first duty is ‘primum non nocere’ (first do no harm). This Latin phrase is commonly misattributed to the Hippocratic oath – in which it does not appear.4 Beyond the mistakes made relating to its origin, clinicians use this phrase in fallacious inflammatory ways in an attempt to shame adversaries into believing they are behaving in an unethical fashion. One could easily turn this argument around and suggest that putting patients on unproven, lifelong immunosuppression in the hope it reduces the risk of a relapse is potentially doing harm. Since azathioprine has a higher rate of lymphoma than mycophenolate mofetil, are my colleagues who prefer azathioprine for NMO breaking a sacred oath? No. Primum non nocere is an important guiding force for physicians, but sometimes it is hard to define what is the most harmful. Is pursuing well-designed placebo-controlled trials with full informed consent, options to leave the trial and a data safety monitoring board more harmful that recommending lifelong immunosuppression to a 20-year-old based on our collective experience? Finally, it is worth noting that our current experience with agents for NMO are completely devoid of the most critical piece of data – safety. Even if the efficacy data was reliable (which it isn’t), none of our retrospective studies have adequately quantified safety. There were no systematic measures of adverse events, serious adverse events, infections or deaths secondary to treatment. How can we defend our empirical data as adequate enough to forego placebocontrolled trials when we might be causing harm in excess of benefit? It is possible that a head-to-head trial of experimental drug X would appear superior to an active comparator and gain approval, but in reality it could be no better than placebo. That outcome would not be fulfilling our obligation to do no harm. On the contrary, we would be perpetuating a dogma that could cause harm for many generations of patients. For all of these reasons, placebo-controlled trials are needed and ethical in NMO.
692 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
BG Weinshenker Dr Greenberg has received consulting fees from Chugai, Novartis, EMD Serono and Medimmune. He has received grant support from the NIH, PCORI, Biogen and the Guthy Jackson Charitable Foundation. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. References 1. Kimbrough DJ, Fujihara K, Jacob A, et al. Treatment of neuromyelitis optica: Review and
recommendations. Mult Scler Rel Dis 2012; 1: 180–187. 2. Gordon PH, Moore DH, Miller RG, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007; 6: 1045–1053. 3. Messe SR, Sansing LH, Cucchiara BL, et al. Prophylactic antiepileptic drug use is associated with poor outcome following ICH. Neurocrit Care 2009; 11: 38–44. 4. Smith CM. Origin and uses of primum non nocere – above all, do no harm! J Clin Pharmacol 2005; 45: 371–377.57 7 MSJ0010.1177/1352458515579217Multiple Sclerosis JournalBM Greenbergresearch-article2015
Placebo Studies should not be Undertaken in Neuromyelitis Optica: Commentary
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
Multiple Sclerosis Journal 2015, Vol. 21(6) 693–694 DOI: 10.1177/ 1352458515580402 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Brian G Weinshenker
Definitive phase 3 clinical trials for neuromyelitis optica (NMO), previously unthinkable, have become feasible and have actually begun in 2014.1 This achievement has resulted because of key advances over the past 15 years, including: (1) definitive diagnosis and separation of NMO from multiple sclerosis in the majority of patients at an early point in the disease before major irreversible disability; (2) recognition of a comprehensive spectrum of disease presentations aided by a specific biomarker, aquaporin-4 IgG; (3) rational selection of treatments based on understanding of the pathogenesis of NMO. However, progress is threatened by conflicting concerns regarding the need for and the acceptability of placebo-controlled clinical trials in NMO. Regulators in different jurisdictions have provided less than consistent guidance, in part due to differing opinions expressed to them by NMO experts on the subject. Palace and Greenberg nicely summarize the issues. Palace argues that the risk of even a single attack of irreversible disability cannot be asked from a patient given current knowledge and that observational studies in NMO and in a variety of other antibodymediated diseases adequately establish a standard of therapy for NMO; “reinventing the wheel” by conducting placebo-controlled studies is unnecessary. Greenberg argues that the evidence from retrospective studies is potentially flawed, backed up by previous experience from other diseases, for which the efficacy of agents presumed to be effective was
disproven in placebo-controlled clinical trials. He contends that the expanding spectrum of NMO does not allow us to assume that the severity of attacks for contemporary NMO is adequately documented in studies of decades ago; furthermore, arguing that current therapies are a standard of treatment ignores their potential safety risks. Theoretically, newer, targeted immunotherapies, such as monoclonal antibodies, may be safer than older less specific immunosuppressive treatments, though long-term studies will be required to establish the safety even of specific agents. Unexpectedly high frequency of certain infections2 and paradoxical autoimmunity3 have been observed with MS monoclonal antibody treatments.
Correspondence to: Brian G Weinshenker Professor of Neurology, Mayo Clinic, 200 First Street SW Rochester, MN 55905, USA. [email protected] Brian G Weinshenker Mayo Clinic, Rochester, USA
The arguments on both sides are meritorious. But what is the path forward? As one who previously espoused Palace’s arguments but has been convinced that placebo-controlled studies for NMO are acceptable under certain circumstances, I was most swayed by the fundamental principle that placebo-controlled trials are the standard for scientific rigor and having such an evidence base at an early point in therapeutic development for a disease is worthwhile. Treatments such as thymectomy for non-thymoma myasthenia gravis have been performed for decades despite no definitive study and continuing controversy about its efficacy.4 Although a clinical trial has been started years after being considered a standard of practice in many centers.5 enrollment has been difficult and did not meet targets. We may
http://msj.sagepub.com 693
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
