Correspondence

Oral Cladribine and Fingolimod for Relapsing Multiple Sclerosis

N Engl J Med 2010; 362:1738-1740May 6, 2010

Article

To the Editor:

In the three trials for relapsing multiple sclerosis (Feb. 4 issue),1-3 a drug of established efficacy was used as a comparison drug in only one trial.1 In the other two trials,2,3 a total of 855 participants were randomly assigned to a placebo group. The studies were conducted concurrently between April 2005 and September 2007. To provide support for the assertions that the FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis) and CLARITY (Cladribine Tablets Treating Multiple Sclerosis Orally) trials were conducted in accordance with the Declaration of Helsinki, additional information is needed.

A number of physician-investigators participating in the FREEDOMS and CLARITY trials also participated in TRANSFORMS (the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis); some members of the steering committees of those trials also served in that capacity for the TRANSFORMS trial. These facts raise additional questions about clinical equipoise in trial design, physician equipoise in the recruitment of particular patients, and the nature of the information provided to potential patient-participants. Since a number of the investigators participating in these two trials were coauthors of an article concerning the ethical use of placebos in trials for multiple sclerosis,4 they were well placed to provide relevant information for Journal readers.5

Howard Mann, M.D.
University of Utah, Salt Lake City, UT
howard.mann@hsc.utah.edu

No potential conflict of interest relevant to this letter was reported.

5 References

1
Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402-415
Full Text | Web of Science | Medline

2
Kappos L, Radue E-W, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401
Full Text | Web of Science | Medline

3
Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362:416-426
Full Text | Web of Science | Medline

4
Polman CH, Reingold SC, Barkhof F, et al. Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment. Neurology 2008;70:1134-1140
CrossRef | Web of Science | Medline

5
Miller FG, Rosenstein DL. Reporting of ethical issues in publications of medical research. Lancet 2002;360:1326-1328
CrossRef | Web of Science | Medline

To the Editor:

In the article by Giovannoni et al. on the effects of cladribine in relapsing–remitting multiple sclerosis, sustained progression of disability for at least 3 months was used as a secondary end point. However, the effect of using such a short duration to confirm progression merits attention, since prevention of progression is the essence of treatment for multiple sclerosis. In this study, there was no sensitivity analysis with the use of data on sustained progression confirmed at 6 months, as in other trials of disease-modifying therapies reported on by Kappos et al. and Polman et al.1 The effect on progression confirmed at 3 months did not necessarily translate into the same effect on progression confirmed at 6 months; only slightly more patients were free of 3-month sustained disability progression in the cladribine groups in this study. Recent research suggests that the optimal duration for confirmation should be 1 year.2 The short duration for confirmation and the relatively small reduction in the risk of 3-month sustained progression of disability may exaggerate the effect of a disease-modifying therapy on disability progression.

Haifeng Li, M.D., Ph.D.
Qingdao University, Qingdao, China
drlhf@163.com

Xu Zhang, M.D., Ph.D.
First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China

No potential conflict of interest relevant to this letter was reported.

This letter (10.1056/NEJMc1002550) was updated on July 14, 2010, at NEJM.org.

2 References

1
Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910
Full Text | Web of Science | Medline

2
Ebers GC, Heigenhauser L, Daumer M, Lederer C, Noseworthy JH. Disability as an outcome in MS clinical trials. Neurology 2008;71:624-631
CrossRef | Web of Science | Medline

Author/Editor Response

We thank Mann for his letter, which raises several important issues, all of which were considered by the steering committees when planning the FREEDOMS and TRANSFORMS studies and by the institutional review boards that approved these studies at the participating institutions.

Most experts in the field agree that placebo-controlled studies can be ethically justifiable with certain restrictions. As summarized in the article by Polman et al.,1 this view was confirmed by a consensus conference held in March 2007 to discuss the previous recommendations by Lublin et al.2 and reconsider the ethics of placebo-controlled trials and their alternatives in multiple sclerosis. An important stipulation was fully informed consent, including discussion of the rationale, benefits, and risks of currently available treatments; this consent was carried out in both fingolimod trials. In addition, both trials required patients to provide written informed consent if on-study relapse or progression on the Expanded Disability Status Scale occurred.

Regarding the selection of patients for the two trials: although the recruitment periods for the overall trials overlapped, in most individual centers, recruitment for the FREEDOMS trial was completed before the beginning of recruitment for TRANSFORMS. Since fingolimod is an oral medication, some participants were interested in the placebo-controlled study but not in the double-dummy, active-control study in which all patients received injections. Also, some patients did not tolerate interferons well.

Jeffrey A. Cohen, M.D.
Cleveland Clinic, Cleveland, OH

Ludwig Kappos, M.D.
University Hospital, Basel, Switzerland

Since publication of their articles, the authors report no further potential conflict of interest.

2 References

1
Polman CH, Reingold SC, Barkhof F, et al. Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment. Neurology 2008;70:1134-1140
CrossRef | Web of Science | Medline

2
Lublin FD, Reingold SC, National Multiple Sclerosis Society (USA) Task Force on Placebo-Controlled Clinical Trials in MS. Placebo-controlled trials in multiple sclerosis: ethical considerations. Ann Neurol 2001;49:677-681
CrossRef | Web of Science | Medline

Author/Editor Response

We acknowledge the ethical issues raised by Mann in relation to placebo-controlled trials. These issues are the subject of the multiple sclerosis–specific international guidelines reported on by Lublin et al.,1 which conclude that placebo-controlled trials are considered ethical provided that the patients give informed consent after having received information about the possibility of treatment with available therapies. In the CLARITY study, specific policies in relation to informed consent were implemented to address these issues. First, a statement in the patient-information sheet specifically acknowledged the existence of licensed disease-modifying therapies and stated that by participating in the study, the subjects could be denying themselves active treatment. Second, study participants had to provide written informed consent after each relapse, confirmed progression, or both. Finally, a rescue group allowed study subjects to receive treatment with a licensed disease-modifying therapy in the study if they had an exacerbation on more than one occasion during a 1-year period or if their disease progressed.

Some patients choose not to receive injectable therapies; if we performed all trials with an active comparison agent, we would have excluded these patients from participating in this trial. People with needle phobia and those in whom injectable agents have failed because of side effects tend to make up the majority of patients who enroll in contemporary placebo-controlled trials. Once oral disease-modifying therapies are licensed, however, it will be very difficult to justify and recruit subjects for placebo-controlled trials. We do not agree with the stance that it is unethical to conduct placebo-controlled trials; it is paternalistic. Are people with multiple sclerosis not capable of making an informed decision about declining the option of receiving a moderately effective, licensed, disease-modifying therapy and volunteering to participate in placebo-controlled trials?

In response to Li and Zhang's query: data on 6-month confirmed disease progression is being obtained as part of an ongoing, exploratory, post hoc analysis. A 96-week study in relapsing multiple sclerosis is underpowered to analyze confirmed progression at 1 year. The descriptive method used by Ebers and colleagues2 in relation to disease progression did not take into account the comparison between treated and untreated groups of patients, and therefore it ignored a treatment effect.

Gavin Giovannoni, M.B., B.Ch., Ph.D.
Queen Mary University of London, London, United Kingdom
g.giovannoni@qmul.ac.uk

Stuart Cook, M.D.
New Jersey Medical School, Newark, NJ

Per Soelberg Sørensen, M.D., D.M.Sc.
Rigshospitalet, Copenhagen, Denmark

for the CLARITY Study Group

Since publication of their article, the authors report no further potential conflict of interest.

2 References

1
Lublin FD, Reingold SC, National Multiple Sclerosis Society (USA) Task Force on Placebo-Controlled Clinical Trials in MS. Placebo-controlled trials in multiple sclerosis: ethical considerations. Ann Neurol 2001;49:677-681
CrossRef | Web of Science | Medline

2
Ebers GC, Heigenhauser L, Daumer M, Lederer C, Noseworthy JH. Disability as an outcome in MS clinical trials. Neurology 2008;71:624-631
CrossRef | Web of Science | Medline

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