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A review of the ethics of the use of placebo in clinical trials for relapsing-remitting multiple sclerosis therapeutics

Multiple Sclerosis and Related Disorders, May 2016, Pages 109 - 112


Randomized placebo-controlled clinical trials have been considered the most rigorous method of evaluating the efficacy of novel treatment interventions. The first effective disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) were approved in the 1990s after a number of pivotal placebo-controlled trials. Since then, the ethics of the continued use of placebo in clinical trials of new DMTs for RRMS has been the subject of repeated policy statements and recommendations by international committees. As further data have accumulated demonstrating a reduction in long-term morbidity and mortality with early initiation of DMT, a growing consensus has emerged that further inclusion of placebo arms in clinical trials of novel RRMS therapies is no longer ethical.


  • Placebo-controlled clinical trials provided critical data for the efficacy of early DMTs.
  • Data have accumulated on the long-term and short-term harms resulting from delaying the initiation of DMT in RRMS.
  • A growing consensus has emerged that placebo-controlled studies for new DMTs for RRMS are no longer ethical.
  • Future evaluation of novel RRMS therapies should minimize risk of such harm through active comparator superiority studies.

Keywords: Multiple sclerosis, Clinical trials, Ethics, Placebo.

1. Introduction

When developing a clinical trial to study the efficacy of a new medical treatment, the first consideration is clinical equipoise: is there a known treatment that has demonstrated superior efficacy to the experimental agent? If a state of ignorance exists about the efficacy of the new agent, a clinical trial may be justified. In the setting of equipoise for an investigational therapy when no established therapy has demonstrated efficacy for the disease being studied, a placebo arm may be ethically justified. The placebo has a long and distinguished role in clinical medicine and research. In controlled clinical trials, inclusion of a placebo arm has been regarded as the most rigorous method to assess the efficacy of putative therapeutic agents. The placebo must be ethically justified and practical. It is ethically justifiable if there is no known effective treatment and practical if its use appears able to produce interpretable results that may answer the question of efficacy. However, once an effective therapy is established, it becomes unethical to treat a human subject with an inferior therapy, such as a placebo, and an alternative trial design, such as an active comparitor, usually is ethically preferable.

In therapeutic trials for the relapsing-remitting phenotype of multiple sclerosis (MS), a placebo arm was essential in the development of effective disease-modifying therapies (DMT). But now that emerging data have demonstrated that DMTs reduce morbidity and mortality in relapsing-remitting multiple sclerosis (RRMS), particularly with early initiation of therapy, a growing consensus holds that it has become unethical to continue to rely on placebo-controlled trials. Alternative clinical trial methodology, such as active comparator superiority studies, may be the most suitable replacement for placebo-controlled trials of new RRMS therapies. Here we review the use of placebo-controlled trials (PCTs) in MS and evolving thought on this subject through position papers and published commentary.

2. Placebo use in clinical research trials

In 1801 John Haygarth documented what may have been the first reported placebo-controlled trial (de Craen et al., 1999). Over the following century, physicians experimented with placebo and observed placebo effects while testing various remedies (de Craen et al., 1999). In the early 1900s, the word placebo in medical writings began to refer to any inert treatment given concurrently to control subjects in clinical trials (de Craen et al., 1999). Because of the power of the placebo effect, randomized PCTs eventually became considered the most rigorous method of evaluating the efficacy of active treatment interventions. The use of placebo controls has remained controversial, however, because of the need for patient deception (Koshi and Short, 2007). Yet placebos have been widely regarded as ethically acceptable in subjects in whom no proven effective therapy existed for their condition and in which sufficient clinical equipoise was present to test if the treatment under study would be effective (Millum and Grady, 2013). Recent discussions on the ethics of placebo have focused on its use in clinical trials for a disease in which a proven therapy already exists (Avins et al, 2012, Ellenberg and Temple, 2000, and Millum and Grady, 2013).

The Declaration of Helsinki, adopted by the World Medical Association in 1964 and updated periodically, is one of the most influential international standards guiding medical research with human subjects (Carlson et al, 2004, Forster et al, 2001, Hellmann et al, 2014, and Millum et al, 2013). Its revision in 2000 (Lewis et al., 2002) specifically addressed the ethics of PCTs in an era of available therapy and stating “the risks, benefits, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists” (Lewis et al., 2002). Subsequent revisions over the following decade refined this recommendation culminating in the 2013 update which restricted the use of placebo, no intervention, or an intervention less effective than “best proven therapy” in clinical trials to only those circumstances in which “patients who receive them will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention” (Hellmann et al., 2014; Millum et al., 2013).

3. Placebo-controlled clinical trials of MS therapeutics

Many of the 13 disease modifying therapies (DMTs) currently approved for use in the United States (US) for RRMS were first studied in large phase III PCTs (English and Aloi, 2015, Lublin, 2005, and Wingerchuk and Carter, 2014). The first DMTs, interferon beta 1-b, glatiramer acetate, and interferon b-1a, were approved after positive PCTs in the 1990s (Lublin, 2005). Discussions of the ethics of further PCTs in this new era of available therapy for RRMS, as well as an evaluation of potential alternative study designs that complied with the 2000 revision of the Declaration of Helsinki, ensued shortly thereafter (Lublin and Reingold, 2001). In 2000, an international “Task Force on Placebo-Controlled Clinical Trials in Multiple Sclerosis” was constituted to provide guidelines for future clinical trials for MS therapeutics (Lublin and Reingold, 2001). This group concluded that for patients who decline treatment with DMT because of potential side effects of available agents, enrollment in PCTs remained ethical with enhancement of informed consent guidelines. The group further concluded that the participation in PCTs also remained ethical using subjects for whom DMT had “failed” and subjects with progressive MS phenotypes lacking efficacy data for DMT.

The group recognized that PCTs of DMTs in “resource restricted” areas of the world, where access to any DMT was unavailable for financial or political reasons, may be ethically acceptable, providing a stipulation that there would be a reasonable expectation that the study drug, if proven effective, would be made available to the host country after completion of the trial. The group reviewed a variety of alternative study designs, concluding that active comparator studies may not be acceptable to regulatory agencies and studies designed to show superiority of a novel therapy were limited by sample size, outcome measures, and cost (Lublin and Reingold, 2001).

As the development of novel DMTs for RRMS subsequently advanced, the ethics of the use of placebo in clinical trials for these therapies was revisited in meetings in 2004, and 2007 resulting in updated position papers and commentaries in MS-related journals. In 2004, an international panel of experts in MS and clinical trials met under the auspices of the US National Multiple Sclerosis Society Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis to once again consider the ethical challenges of clinical trials of new therapies as a result of the availability of multiple DMTs for MS (McFarland and Reingold, 2005). The group concluded that because DMTs were only partially effective for RRMS and associated with side effects that resulted in compliance challenges, there remained a need to develop new agents.

Acknowledging the ethical concerns surrounding use of PCTs for such agents, the group deliberated the pros and cons of a large number of alternative trial designs but reached no consensus on an optimal alternative. Non-inferiority, equivalency and superiority studies, against available DMTs were considered the most practical means to determine safety and comparative efficacy data between available and emerging therapies. However, the need for a larger sample size and the potential difficulty finding a commercial sponsor for such studies were recognized as challenges. During this time, the first monoclonal antibody to treat RRMS was approved after a pivotal phase III study that included 315 patients who received placebo by intravenous infusion every four weeks for more than two years (Polman et al., 2006).

In 2007, under the auspices of its International Advisory Committee on Clinical Trials of New Agents in MS, the US National MS Society again convened a group to re-examine the ethics of PCTs (Polman et al., 2008). This group concluded that PCTs trials in MS remained ethical, but required additional limitations. They asserted that placebo-controlled trials were ethically justified when the outcomes of placebo therapy “do not increase the risk of serious or irreversible harm”. PCTs were also viewed as ethical when subjects with RRMS chose not to take available therapies, with the caveat of carefully specified improvement in informed consent procedures in these situations and emphasis that such trials were not to be presented as an alternative to proven therapies.

To avoid bias and potential patient confusion between clinical care and research, the group also recommended, when possible, to employ separate research physicians to lead the consent process other than the patient's usual treating physician. The group also noted it was permissible to offer enrollment in PCTs to those patients who had “failed” proven therapies, presuming all classes of DMTs had been tried before participation was offered. PCTs or therapies for primary progressive MS and secondary progressive MS were considered ethical because there were no proven therapies for these conditions with the exception of a single therapy for the latter with limited availability in some countries.

Due to the increasing difficulty of recruitment for PCTs in North America and Europe, the group noted a growing reliance on countries in which there was limited or absent access to proven DMTs for economic or regulatory reasons. They asserted that for these trials to proceed ethically, “a fair distribution of benefits as well as burdens no matter what the geographic or economic environment” should be ensured (Polman et al., 2008). As a result, the group stipulated that industry sponsors of such trials must specify a commitment to post-trial access to treatments found beneficial in the trial and for post-trial clinical care in resource-limited environments. The group reviewed a number of alternative trial designs. Defining a tolerable difference between the two agents under study as well as assessments of safety and efficacy were present challenges noted for non-inferiority studies.

The group also noted that while a DMT found more effective than placebo in a prior trial might presumably aid in determining if two agents are equally ineffective, disease phenotype may differ significantly between study populations in different trials thus confounding such an assessment. The group concluded that non-inferiority studies should be considered unethical until comparability could be demonstrated between outcomes of previous placebo-controlled trials and performance of an active comparator in new trials. Presuming equipoise suggests the superiority of a novel therapy, studies comparing such a therapy with a proven effective DMT appeared best to provide data for comparative outcomes against a standard of care while ensuring that all subjects have the possibility of treatment with either a proven effective DMT or a potential new therapy. Such designs were also noted to present challenges such as assessment of absolute (rather than relative) safety and efficacy of the experimental therapy.

After publication of this policy statement in 2008, several studies evaluating new DMTs for RRMS were published that included large groups of subjects receiving placebo, increasingly drawn from resource-restricted areas. Although recruitment for some of these studies may have begun prior to 2008, in 2010, 2012, and 2013, the oral therapies fingolimod, teriflunomide, and dimethyl fumerate were approved in the US after the completion of pivotal international PCTs (Fox et al, 2012, Gold et al, 2012, Kappos et al, 2010, and O’Connor et al, 2011). During these two-year studies, approximately 1500 patients with RRMS were randomized to placebo treatment (Fox et al., 2012;Gold et al., 2012;Kappos et al., 2010; O’Connor et al., 2011). Two of these new DMTs were also studied in a phase III trial with an active comparator arm (Cohen et al., 2010; Fox et al., 2012). Several subsequent commentaries addressed this continued use of placebo in these clinical trials of novel therapies for RRMS.

In 2013, Garattini and colleagues wrote an opinion article concerning the continued use of placebo in MS (Garattini et al., 2013). They noted that, in spite of the above policy recommendations published in 2001, 2005, and 2008, in 10 phase III clinical trials for RRMS therapies since the Declaration of Helsinki revision of 2000, as many as 2752 patients received placebo, resulting in more than 4800 patient-years of exposure. They highlighted that in the methodology descriptions, none of these studies explicitly provided a rationale for placebo or details justifying its ethical use. They estimated that these patients cumulatively suffered approximately 630 more MS relapses than those treated with conventional DMT in these trials, and suffered significantly more disability progression and accumulation of MRI detectable MS lesions associated with CNS damage. Garattini et al. highlighted that existing DMTs approved at the time of these studies had shown efficacy, low risk for toxicity, and the new agents under study were not exclusively tested in patients resistant or intolerant to these DMTs. They questioned whether the informed consent forms in these trials specified that placebo was given in place of a proven effective DMT. Garatini et al. concluded that placebo use in these clinical trials unjustifiably harmed research subjects who were deprived of proven effective DMT and advocated for active comparator studies for the evaluation of new MS therapies.

Emerging data published during and after the policy statement by the International Advisory Committee on Clinical Trials of New Agents in MS in 2008, particularly from long-term follow up of pivotal placebo-controlled trials of DMT for RRMS, increasingly supported the criticisms of Garattini and colleagues. These studies showed an association with morbidity from disability as well as permanent CNS damage, and potential increased risk of long term mortality, resulting from a delay in the initiation of DMT for RRMS by use of placebo (Edan et al., 2014;Garattini et al., 2013; Goodin et al, 2012, Kennedy, 2013, and Noyes and Weinstock-Guttman, 2013).

In 2014, experienced MS clinicians published commentaries in a prominent MS-related journal concerning the ethics of continued PCTs of DMT in RRMS (Hawkins, 2014, Hutchinson, 2014, and Zajicek, 2014). While acknowledging that equipoise for PCTs had diminished, Zajicek suggested that treatment stratification or “personalized medicine” for individual patients may comprise a situation in which placebo use ethically justifies a determination of which DMT best benefits a specific patient with the least risk. He argued for the continued value of placebo by highlighting the limits of previously published natural history cohorts collected decades earlier, when the diagnosis and understanding of the disease was less developed, and recent changes observed in the natural history of RRMS (Zajicek, 2014). By contrast, Hawkins argued that data from recent pivotal trials in RRMS suggested that exposure to placebo and delay in the initiation of proven effective DMT resulted in irreversible harm to the placebo group and suggested that new agents should be tested against 'best available treatment' as a matter of “good ethical practice” (Hawkins, 2014).

Hutchinson, the editor for the commentary, agreed with Hawkins, arguing that equipoise simply no longer exists for placebo-controlled trials of new therapies for RRMS in our contemporary era in which a number of established therapies have short and long-term benefits reducing disability and death (Hutchinson, 2014). Hutchinson suggested that investigators should transition to active comparator trials for evaluation of DMTs and concluded that “the period of placebo-controlled trials in relapsing multiple sclerosis has now ended”.

In November 2014 after several pivotal active comparator trials, and for the first time without a cohort of subjects receiving placebo, a new DMT, alemtuzumab, was approved in the US for use in RRMS (Cohen et al, 2012, Coles et al, 2008, and Coles et al, 2012). The approval of alemtuzumab demonstrated that active comparator studies could be both ethical and practical, and were considered valid by regulatory authorities. But such trials are not free of ethical concerns. The exposure of a larger number of subjects to potentially inferior treatment particularly for the longer duration required to demonstrate superiority is an acknowledged challenge. The ethics of continued use of a specific DMT that has repeatedly demonstrated inferior efficacy in prior trials as an active comparator in future trials has also engendered discussion. However the era of the study of therapeutics for RRMS without PCTs appears to have arrived. Data were presented in October 2015 for ocrelizumab, a new agent for RRMS, demonstrating efficacy in two phase III active comparator studies (Fyfe, 2015 and Sastre-Garriga and Wiendl, 2016) and numerous ongoing and anticipated active comparator trials for RRMS are now registered with As PCTs for the study of RRMS disappear, such trials may remain ethical for the progressive phenotypes of this disease. The decade-long evolution of thought on the ethics of use of PCTs in RRMS may inform the design and implementation of these trials, as well as future active-comparitor trials for RRMS.

4. Conclusion

Placebo-controlled clinical trials provided critical data for the efficacy of early DMTs for RRMS. Expert groups analyzing the ethics of placebos in trials of novel MS therapies increasingly argued for their constrained use, exceptions for recruitment in resource-limited regions, and employment of alternative study designs. As data have accumulated on the long-term and short-term harms resulting from delaying the initiation of DMT, a growing consensus has emerged that placebo-controlled studies for new DMTs for RRMS are no longer ethically justified and that any future evaluation of novel RRMS therapies should minimize such risk of such harm through active comparator superiority studies.

Conflicts of interest and funding

Andrew J Solomon received a research grant from the National Multiple Sclerosis Society and was a primary investigator in a multicenter clinical trial for a medication sponsored by Biogen Idec.

James L Bernat serves on the editorial boards of Neurocritical Care, Neurology Today, and Multiple Sclerosis and Related Disorders (all unpaid) and the Physician's Index for Ethics in Medicine (paid). He receives royalty payments for Ethical and Legal Issues in Neurology (Elsevier, 2013), Ethical Issues in Neurology 3rd ed (Lippincott Williams and Wilkins, 2008), and Palliative Care in Neurology (Oxford University Press, 2004).


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a Department of Neurological Sciences, University of Vermont, Burlington, VT 05401, USA

b Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA

Corresponding author.

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