Ethical challenges in paediatric clinical trials in ... - SAGE Journals

437360

2012

TAN531756285612437360SN TenembaumTherapeutic Advances in Neurological Disorders

Therapeutic Advances in Neurological Disorders

Ethical challenges in paediatric clinical trials in multiple sclerosis

Review

Ther Adv Neurol Disord (2012) 5(3) 139–146 DOI: 10.1177/ 1756285612437360 © The Author(s), 2012. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav

Silvia N. Tenembaum

Abstract: Children and adolescents with multiple sclerosis (MS) are reported to show high rates of relapse early in the course of the disease as well as cognitive deterioration over time. Immunomodulatory therapies developed for adult MS patients are currently the standard first-line agents for most paediatric MS patients. Available data indicate that the three interferon-beta preparations and glatiramer acetate are safe and well tolerated in children and adolescents with MS, and provide preliminary indications of efficacy in terms of relapse rate reduction. However, these treatments are only partly effective and their routes of administration can be bothersome, particularly for children. Emerging therapies for MS offer promise for improved disease control and long-term clinical outcome, with the advantage of an oral administration for some of them. The future approval of these new medications requires clinical trial consideration of such therapies in the paediatric population. Many of these new agents carry a higher risk for serious adverse events with increased toxicity and still undefined long-term side effects. There are ethical issues as well as issues related to feasibility that must be borne in mind when planning investigation trials for new pharmacological agents in the paediatric population, including immunological maturity, key period of exposure to numerous community-acquired infections, neurodevelopmental factors, in addition to shortterm and long-term age-related toxicities. Furthermore, the lack of a large enough paediatric MS population worldwide limits some designs and the feasibility of participation in all the studies. Emerging new therapies have the potential to optimize the care of both paediatric and adult patients with MS. Future treatment trials in children and adolescents with MS will require a multicentre design, definition and selection of key outcome measures, and identification of the most promising therapies. Risks versus benefits of each specific treatment should be weighed and comprehensively discussed. Keywords: adolescence, childhood, clinical trials, ethics, immunomodulatory treatment, immunosuppression, multiple sclerosis, new therapies, recruitment

Introduction Paediatric-onset multiple sclerosis (MS) has been a focus of great interest in recent years and an increasing number of studies are dedicated to the delineation of the characteristics of the disease in this age group. Approximately 3–5% of MS patients experience their first attack during childhood [Duquette et al. 1987; Ghezzi et al. 1997; Boiko et al. 2002; Chitnis et al. 2009]. Class I level evidence for a reduction in relapse frequency in adults with MS has led to the use of interferon beta and glatiramer acetate in children.

Currently the available disease-modifying therapies (DMTs) are known to be only partially effective in adults with MS. Little is known about paediatric patients with MS, but inadequate treatment response to first-line DMTs, such as persistent relapses and disease progression, has been reported by treating physicians in 30–44% of children [Ghezzi et al. 2009;Yeh et al. 2011]. These reported findings highlight the importance of establishing an accurate definition for inadequate treatment response in paediatric patients with MS, and the need for new therapeutic options in these patients [Chitnis et al. 2012].

Correspondence to: Silvia N. Tenembaum, MD Staff Neurologist, Department of Neurology, National Pediatric Hospital Dr Juan P. Garrahan, Billinghurst 850. Buenos Aires, 1174 Argentina silviatenembaum@gmail. com

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Therapeutic Advances in Neurological Disorders 5 (3) All first- and second-line MS therapies used in children and adolescents are off-label since immunomodulatory therapies currently approved for adults with MS have not been formally evaluated by clinical trials in children [Tenembaum, 2010; Kuntz et al. 2010; Ghezzi, 2010; Banwell et al. 2011]. However, consensus recommendations regarding the use of existing first- and second-line therapies, as well as the evaluation of new therapies in paediatric patients with MS, have recently been published by the International Pediatric Multiple Sclerosis Study Group (IPMSSG) [Chitnis et al. 2012]. New therapeutic strategies are currently being tested or have been approved recently for adult patients with MS (Table 1), including oral therapies and monoclonal antibodies. Some seem to have a stronger clinical impact comparing published data with current first-line therapies for MS (although head-to-head trials are lacking), while others offer the convenience of oral administration; however, their long-term safety profiles have yet to be established [Coles et al. 2008; Hauser et al. 2008; Killestein et al. 2011]. Some of these new agents might play an important role in the treatment of paediatric patients with MS, but it will be necessary to start evaluating how such therapies might be tested in paediatric patients. There are ethical as well as feasibility issues that must be borne in mind when planning investigation trials for new pharmacological agents in the paediatric population. General ethical issues in human research Phase I and phase II trials are the first stage of drug development testing in human subjects. These stages are rarely performed initially in children, as a safe dose is established in adult patients, except when a disease is exclusive to the paediatric population. There are strict ethical principles established for medical research involving human subjects. The internationally accepted requirements have been constituted in the Nuremberg Code of 1947, the Declaration of Helsinki [World Medical Association, 2008], first adopted in 1964, the Belmont Report of 1979 [US Department of Health, Education, and Welfare], and the Principles of Biomedical Ethics developed in the 1970s [Beauchamp and Childress, 2009]. The Belmont Report settles on the three key principles of ethical trial conduct: respect for persons, beneficence and justice.

(1) Respect for persons recognizes the need for voluntary informed consent and adequate patient information about the research aims, methods, anticipated benefits and potential risks of the study, and the procedures that will be carried out. This principle of patient autonomy is of extraordinary importance, particularly in the case of studies including children. (2) The second principle involves the analysis of benefits and risks and harms. A reasonable and critical weighing of risks and benefits of a new intervention against those of the best current proven interventions before starting a trial is indispensable. (3) Finally, the concept of justice deals with the fair selection of participants in a study. There should be no other reasons other than scientific or ethical ones for including children in research [Henschel et al. 2010]. Ethical issues regarding investigation trials in children Ethics on recruitment One aspect of paediatric investigation plans to be considered in the first place is the need for voluntary informed consent. Children may not have the autonomy to decide whether to participate in a trial or to refuse participation. Following the Declaration of Helsinki they are considered ‘“legally incompetent’”, and the physician must seek informed consent from the legally authorized representative. Therefore, parents or legal guardians have to consent in the best interest of the child. However, institutional review boards at most institutions request assents to be signed by children, thus involving them in the decision process. The definition of the age of consent is a controversial topic. The European Union refers to the principle of respect for autonomy in its Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the Paediatric Population [European Union, 2008]. This document considers that children with normal cognitive competence are able to express assent or denial of participation in a research project at about the age of 7 years. Nevertheless, the Ethics Working Group of the Confederation of European Specialists in Paediatrics considers that the ability to understand the possible benefits and risks of a research study can be expected at the earliest from the age of 9 years onward [Gil, 2004]. To be

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SN Tenembaum Table 1. Main adverse events reported for emerging multiple sclerosis therapeutics. Agents

Route and dose

Presumed mechanism of action

Adverse events

Monoclonal antibodies Alemtuzumab [Coles et al. 2008; Cossburn et al. 2011]

12 or 24 mg i.v., 5 days consecutively initially, followed by 12 mg i.v., 3 days consecutively 1 year later

Anti- CD52 antibody Prolonged suppression of CD4+ T cells

Acute cell lysis with cytokine release syndrome Autoimmune thyroid disorders (Graves disease) Immune thrombocytopaenic purpura (including one fatal case) Goodpasture’s syndrome Common infections (upper respiratory and urinary tract infections, herpes zoster after reactivation of varicella zoster virus) Vitiligo, bullous skin rash Possibly increased incidence of secondary malignancies

Rituximab [Hauser et al. 2008; Naismith et al. 2010]

Ocrelizumab [Kappos et al. 2011]

Ofatumumab [Taylor et al. 2011]

Daclizumab [Wynn et al. 2010]

375 mg/m2 i.v. weekly × 4 weeks

Anti -CD20 monoclonal Ab Circulating B-cell depletion Reduced antigen Presentation

600 or 2000 mg i.v., 2 weeks apart initially, followed by 600 mg, 1000 mg or placebo on weeks 24 and 26

Anti- CD20 monoclonal Ab

100, 300 or 700 mg, in two treatment courses (2 × 2 i.v. infusions)

IgG1kappa lytic monoclonal Ab, inducing a potent B-cell lysis

2 mg/kg subcutaneously every 2 or 4 weeks, for 24 weeks

interleukin-2 Rα antibody Anti-CD25 antibody

Infusion-related: fever, chills and occasional hypotension, dyspnoea Infection PML (only seen in combination with immunosuppressants in two patients with SLE) Systemic inflammatory syndrome Serious opportunistic infections (including fatal cases) (from a phase lll rheumatoid arthritis trial in combination with immunosuppressants) Common infections: influenzalike illness, upper respiratory and urinary tract infections, nasopharyngitis. Rash and urticaria Angioedema Fatal interstitial lung disease Diarrhoea and pneumonia Pericardial effusion (from a study in patients with active rheumatoid arthritis) Serious skin rash Serious infections Liver function test abnormalities Fatal autoimmune hepatitis In situ breast carcinoma (Continued)


Therapeutic Advances in Neurological Disorders 5 (3) Table 1. (Continued) Agents

Route and dose

Presumed mechanism of action

Adverse events

240 mg twice a day, or three times a day

Induces activation of the nuclear factor E2-related factor-2 pathway Neuroprotection via NFk B pathway Drug-induced shift towards a more anti-inflammatory cytokine profile (Th2) and adhesion molecule expression

Facial flushing Headache Gastrointestinal side effects

Fingolimod (FTY720) [Cohen and Chun, 2011; Khatri et al. 2011]

0.5 mg once daily

Sphingosine-1phosphate receptor modulator Immune cell sequestration

Lymphocytopaenia Cardiac disorders (bradycardia, atrioventricular conduction block, hypertension) Common infections (nasopharyngitis) Serious infections ( exacerbation of herpes virus infection, including two fatal cases) Macular oedema Hepatoxicity Back pain Possible increased incidence of secondary malignancies (localized skin cancers and ovarian cancer)

Laquinimod

0.6 mg daily

Immunomodulatory Derivative of linomide Induces a cytokine shift towards T-helper-2 and Th3 cytokines

Liver enzyme elevation (transient, asymptomatic) Gastrointestinal symptoms Back pain, arthralgia Possible venous thrombosis

Teriflunomide

7 or 14 mg daily

Active metabolite of leflunomide Inhibitor of pyrimidine synthesis by reducing the activity of mitochondrial enzyme dihydro-orotate dehydrogenase

Hepatotoxicity (fatal liver failure with leflunomide) PML (in a patient with SLE with leflunomide) Common infections Headaches Alopecia Rhabdomyolysis Teratogenic effects of leflunomide

Oral therapies [Killestein et al. 2011] BG-12 ( dimethyl fumarate)

Ab, antibody; i.v., intravenous; PML, progressive multifocal leucoencephalopathy; SLE, systemic lupus erythematosus.

able to assent to trial children need to be informed in detail about the research procedures and methods. Consequently, their assent should be sought using age-appropriate information.

Another ethical as well as practical and scientific issue concerns the number of paediatric patients available for a study. On the one hand, for ethical reasons, the sample size should be kept as small as


SN Tenembaum possible in order to include no more patients in a trial than necessary with the objective of minimizing unnecessary risks. On the other hand, the sample size should be large enough to have a significant impact on study power. An independent reason for a small sample size is the infrequency of a particular paediatric disease. Several large series report prevalence rates of paediatric-onset MS at 2.2 –4.4% of all MS cases [Ghezzi et al. 1997; Boiko et al. 2002; Renoux et al. 2007; Chitnis et al. 2009]. Population-based studies suggest even lower rates, with paediatric MS accounting for only 1.7% of MS cases [Fromont et al. 2010; Klein et al. 2010]. The lack of a large enough paediatric MS population worldwide limits some designs and the feasibility of participation in all the studies, due to the competitive setting of multiple potential investigations into different emerging medications. Ethical use of placebo Regulatory and ethical guidelines emphasize that in some instances the thoughtful use of placebo remains essential to determine the efficiency of new medical interventions. Placebo-controlled clinical trials have long served as the standard design for MS clinical studies. However, the ethics of such clinical trials in an era of available established therapies have been widely discussed, triggered by revisions to the Declaration of Helsinki in 2000. Consequently, an international group of MS specialists, ethicists, statisticians, representatives from the regulatory agencies and from the pharmaceutical industry met in 2006 to reconsider recommendations regarding the ethics of placebo-controlled trials in MS [Polman et al. 2008a]. The group concluded that placebo-controlled trials can still be performed ethically, but with restrictions. The following indications were considered ethically justifiable: (a) when the outcomes of placebo therapy do not increase the risk of serious or irreversible harm, as in clinical trials of symptomatic agents; (b) in forms of the disease for which there is no established effective therapy, including primary progressive MS and secondary progressive MS in which relapses are no longer present; (c) when there is an established effective therapy, placebo-controlled trials of novel agents are ethical in subjects who have not responded to those established therapies.

Placebo-controlled trial design requires that some study individuals forego active or possibly effective therapy. In addition, this model of trial requires large cohorts of patients, large enough to generate valid evidence. Nevertheless, this prerequisite is well beyond the numbers achievable in the paediatric MS context. Ethical considerations of alternatives to placebo-controlled trials Among the most prominent of alternative designs for MS clinical trials are add-on and active comparator arm studies. Active comparator arm studies use either a noninferiority or superiority design to compare outcomes of treatment with an established therapy against a novel therapy. In this study design there is no risk of placebo treatment, but a 10-fold increase in sample size is needed for an active comparator study compared with a placebo-controlled study to obtain an endpoint or answer [Polman et al. 2008 b]. Increasing the numbers of patients exposed to potential danger or lack of efficacy of the novel agent may result in an ethical challenge, particularly when the study includes paediatric patients. In add-on studies a novel or experimental agent or its placebo control are added to an established therapy. Add-on studies are feasible and ethically acceptable, especially if the novel treatment has a potentially synergistic or additive biological mode of action [Polman et al. 2008a]. Patients who have had a suboptimal response to first-line therapies may be the best candidates for this kind of study. Nevertheless, such trials may only provide information for a subgroup of partial nonresponders, a study group that may differ from a treatmentnaïve population (Polman et al. 2008a). Other alternative designs to placebo-controlled trials are attractive, but each presents its own practical and ethical considerations. Dose-ranging studies that aim to avoid the use of placebo by offering one or more dose arms that are subtherapeutic as a control are no more ethical than are placebo-controlled studies. In deferred- treatment arm studies, one or more groups are randomized initially to short-term placebo followed by the investigational agent compared with the investigational agent from the start. However, the potential risk of remaining on placebo, even over the short term, should be considered to justify such a design.


Therapeutic Advances in Neurological Disorders 5 (3) Adaptive randomization, a study design in which the proportion of patients assigned to placebo changes as information is gathered, is an alternative way to reduce the number of subjects receiving placebo. However, reducing the number of subjects exposed to placebo does not ensure the ethics of such a trial design [Polman et al. 2008a]. Phase IV studies can generate a sufficient amount of pharmacokinetic (PK) and pharmacodynamic (PD) information as well as safety data for drugs already approved or about to be approved in adults. The PK and PD data of a particular agent and the potential differences in children and adolescents should be taken into account when considering use and dosing in paediatric MS patients [Chitnis et al. 2012]. Ethics committee with paediatric expertise Any clinical trial may be undertaken only if an ethics committee has legitimated the protocol. Different aspects of a clinical trial, such as the relevance and advantages of the study, risk/benefit ratio, quality of the institution and expertise of the researchers involved, must be evaluated by an independent body of health professionals. This is especially true among paediatric patient populations. In the case of multicentre clinical trials, the single opinion of an ethics committee must be given for each researcher’s site and state involved in the multicentre trial. Ethics committees are in general heterogeneous, thus offering multiple views and judgements. As an example, a survey was carried out among European ethics committees to evaluate the impact of the new European paediatric regulatory framework and to assess their involvement and interest in paediatric research [Altavilla et al. 2012]. Results showed a lack of knowledge, understanding, awareness and involvement of ethics committees in paediatric research, especially in terms of training and education. Nevertheless, the majority of participants expressed interest in future initiatives related to paediatric research. Therefore, using an international network may be essential to enhance the work of ethics committees in paediatric research. In addition, the selection of an ethics committee coordinator/facilitator, ethically and economically independent from the sponsors of the study, would guarantee the quality of discussions during the evaluation process [Knellwolf et al. 2011].

The most challenging area in paediatric MS is the identification of therapeutic strategies and safe agents that target relevant disease processes. At present, there are no regulatory agency-approved therapeutics for paediatric MS in North America or Europe, even though the approval of the regulatory agency in Europe restricts administration of DMTs to patients 12 years of age and older. Strategies to evaluate systematically the place of individual therapies in the armamentarium of the treating physician are needed. Immunomodulatory agents target an important disease process, however, additional strategies are required to prevent progressive disability and enhance repair of the damaged nervous system in children with MS. Targeting those molecules that play a key role in the pathogenesis of inflammatory demyelination of the central nervous system might be a strategy to reverse acquired disability in MS. Conclusion and recommendations The inclusion of paediatric patients in MS trials evaluating new therapeutic agents is essential to reduce the use of medications that are currently off-label, and to ensure that children are exposed to safe as well as effective treatments [Knellwolf et al. 2011; Henschel et al. 2010]. Nevertheless, there is an urgent need to update the methodology used to conduct clinical trials in paediatric patients, as well as to define validated endpoints for these studies. Emerging therapies should be evaluated in pediatric MS in the context of carefully designed multicentre clinical trials with standardized clinical, biological and neuroimaging evaluations, including the identification of the most promising therapies [Chitnis et al. 2012]. All paediatric MS clinical trials and situations in which clinical trials may not be feasible due to restricted indications, should include a long-term prospective registry capturing valuable information on both short- and long-term safety and tolerability [Chitnis et al. 2012] . Probably the best way to achieve all the aforementioned ethical challenges in paediatric clinical trials will be through a consensus meeting including an international group of paediatric and adult MS specialists, ethicists and statisticians, in addition to representatives from the regulatory agencies and the pharmaceutical industry, where the concept of clinical trials in children and adolescents with MS is addressed


SN Tenembaum by workgroups discussing recommendations on design and outcome measures in paediatric MS. One of the aims of the IPMSSG is to support these initiatives. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Conflict of interest statement The author declares no conflicts of interest in preparing this article.

References Altavilla, A., Manfredi, C., Baiardi, P., DehlingerKremer, M., Galletti, P., Alemany, A. et al. (2012) Impact of the new European paediatric regulatory framework on ethics committees: overview and perspectives. Acta Paediatr 101: e27–e32. Banwell, B., Bar-Or, A., Giovannoni, G., Dale, R.C.and Tardieu, M. (2011) Therapies for multiple sclerosis: considerations in the pediatric patient. Nat Rev Neurol 7: 109–122. Beauchamp, T.L. and Childress, J.F. (2009) Principles of Biomedical Ethics. Oxford: University Press. Boiko, A., Vorobeychik, G., Paty, D., Devonshire, V. and Sadovnick, D.; University of British Columbia MS Clinic Neurologists. (2002) Early onset multiple sclerosis: a longitudinal study. Neurology 59: 1006–1010. Chitnis, T., Glanz, B., Jaffin, S. and Healy, B. (2009) Demographics of pediatric-onset multiple sclerosis in an MS center population from the Northeastern United States. Mult Scler 15: 627–631. Chitnis, T., Tenembaum, S., Banwell, B., Krupp, L., Pohl, D., Rostasy, K. et al.; for the International Pediatric Multiple Sclerosis Study Group. (2012) Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler 18: 116–127. Cohen, J.A. and Chun, J. (2011) Mechanisms of fingolimod’’s efficacy and adverse effects in multiple sclerosis. Ann Neurol 69: 759–777. Coles, A.J., Compston, D.A., Selmaj, K.W., Lake, S.L., Moran, S., Margolin, D.H. et al. 2008) Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 359: 1786–1801. Cossburn, M., Pace, A.A., Jones, J., Ali, R., Ingram, G. and Baker, K. (2011) Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology 77: 573–579.

Duquette, P., Murray, T.J., Pleines, J., Ebers, G.C., Sadovnick, D., Weldon, P. et al. (1987) Multiple sclerosis in childhood: clinical profile in 125 patients. J Pediatr 111: 359–363. European Union. (2008) Ethical considerations for clinical trials on medicinal products conducted with the paediatric population. Eur J Health Law 15: 223–250. Fromont, A., Binquet, C., Sauleau, E.A., Fournel, I. Bellisario, A., Adnet, J. et al. (2010) Geographic variations of multiple sclerosis in France. Brain 133 1889–1899. Ghezzi, A. (2010) Therapeutic strategies in childhood multiple sclerosis. Ther Adv Neurol Disord 3: 217–228. Ghezzi, A., Amato, M.P., Annovazzi, P., Capobianco, M., Gallo, P., La Mantia, L. et al. (2009) Long-term results of immunomodulatory treatment in children and adolescents with multiple sclerosis: the Italian experience. Neurol Sci 30: 193–199. Ghezzi, A., Deplano, V., Faroni, J., Grasso, M.G., Liguori, M., Marrosu, G. et al. (1997) Multiple sclerosis in childhood: clinical features of 149 cases. Mult Scler 3: 43–46. Gill, D. (2004) Ethical principles and operational guidelines for good clinical practice in paediatric research. Recommendations of the ethics working group of Confederation of European Specialists in Paediatrics (CESP). Eur J Pediatr 163: 53–57. Hauser, S.L., Waubant, E., Arnold, D.L., Vollmer, T., Antel, J., Fox, R.J. et al. (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis.N Engl J Med 358: 676–688. Henschel, A.D., Rothenberger, L.G. and Boos, J. (2010) Randomized clinical trials in children – ethical and methodological issues. Curr Pharm Des 16: 2407–2415. Kappos, L., Li, D., Calabresi, P.A., O’Connor, P., Bar-Or, A., Barkhof, F. et al. (2011) Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 378: 1779–1787. Khatri, B., Barkhof, F., Comi, G., Hartung, H.P., Kappos, L., Montalban, X. et al. (2011) Comparison of fingolimod with interferon beta-1a in relapsingremitting multiple sclerosis: a randomized extension of the TRANSFORMS study. Lancet Neurol 10: 520–529. Killestein, J., Rudick, R.A. and Polman, C.H. (2011) Oral treatment for multiple sclerosis. Lancet Neurol 10: 1026–1034. Klein, N.P., Ray, P., Carpenter, D., Hansen, J., Lewis, E., Fireman, B. et al. (2010) Rates of


Therapeutic Advances in Neurological Disorders 5 (3) autoimmune diseases in Kaiser Permanente for use in vaccine adverse event safety studies. Vaccine 28: 1062–1068. Knellwolf, A.L., Bauzon, S., Alberighi, O.D., Lutsar, I., Bácsy, E., Alfarez, D. et al. (2011) Framework conditions facilitating paediatric clinical research. Ital J Pediatr 37: 12. Kuntz, N.L., Chabas, D., Weinstock-Guttman, B., Chitnis, T., Yeh, E.A., Krupp, L. et al. (2010) Treatment of multiple sclerosis in children and adolescents. Expert Opin Pharmacother 11: 505–520. Naismith, R.T., Piccio, L., Lyons, J.A., Lauber, J., Tutlam, N.T., Parks, B.J. et al. (2010) Rituximab add-on therapy for breakthrough relapsing multiple sclerosis. A 52-week phase II trial. Neurology 74: 1860–1867. Polman, C.H., Reingold, S.C., Barkhof, F., Calabresi, P.A., Clanet, M., Cohen, J.A. et al. (2008) Ethics of placebo-controlled clinical trials in multiple sclerosis. A reassessment. Neurology 70: 1134–1140. Polman, C.H., Reingold, S.C., Barkhof, F., Calabresi, P.A., Clanet, M., Cohen, J.A. et al. (2008) Ethics of placebo-controlled clinical trials in multiple sclerosis. Appendix e-3. Example of sample size calculation for placebo versus active-arm comparator trials. Neurology 70: 1–2.

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Renoux, C., Vukusic, S., Mikaeloff, Y., Edan, G., Clanet, M., Dubois, B. et al. (2007) Natural history of multiple sclerosis with childhood onset. N Engl J Med 356: 2603–2613. Taylor, P.C., Quattrocchi, E., Mallett, S., Kurrasch, R., Petersen, J. and Chang, D.J. (2011)

Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naïve, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, doubleblind, placebo-controlled clinical trial. Ann Rheum Dis 70: 2119–2125. Tenembaum, S.N. (2010) Therapy of multiple sclerosis in children and adolescents. Clin Neurol Neurosurg 112: 633–640. US Department of Health, Education, and Welfare. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979) The Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects of Research. http://ohsr.od.nih. gov/guidelines/belmont.html World Medical Association. (2008) Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects; 59th WMA General Assembly, Seoul. http://www.wma.net/ en/30publications/10policies/b3/index.html Wynn, D., Kaufman, M., Montalban, X., Vollmer, T., Simon, J., Elkins, J. et al. (2010) Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol 9: 381–390. Yeh, E.A., Waubant, E., Krupp, L.B., Ness, J., Chitnis, T., Kuntz, N. et al. (2011) Multiple sclerosis therapy in pediatric patients with refractory multiple sclerosis. Arch Neurol 68: 437– 444.
