Mar 26, 2008
Conducting placebo-controlled studies in people with relapsing MS can be done ethically when specific criteria have been met, according to recommendations from an international panel convened by the National MS Society. The use of placebos – “dummy” medications – as a control group for experimental therapies when there are multiple agents available to treat relapsing forms of MS has been of growing concern The updated recommendations are based on a 2007 meeting held under the auspices of the Society’s International Advisory Committee on Clinical Trials in MS, and are published in a special supplement of Neurology dedicated to MS (2008;70:1134).
Background: Using placebo as a control has been the historic “gold standard” for clinical trials in MS, and permits potential benefits – or safety issues – of an experimental treatment to emerge in high relief against a control group that receives the same amount of physician care except for inactive therapy. Ethical concerns exist, however, when there are approved disease-modifying therapies, such as in relapsing forms of MS, which are known to be relatively safe and effective.
A previous summit convened by the Society published its recommendations in 2001 (Annals of Neurology 2001;49:677-681). These guidelines laid out specific circumstances in which it could be considered ethical to conduct placebo-controlled trials in MS. The new panel met to revisit those guidelines in light of today’s therapy and clinical trials landscape. The expanded meeting of the International Advisory Committee on Clinical Trials in MS, chaired by Chris H. Polman, MD, PhD (Free University Medical Center, Amsterdam), engaged MS physicians, ethicists, drug regulatory authorities, statisticians, industry representatives and clinical trial experts who study other diseases facing similar issues debated complex pros and cons of placebo controls in the context of approved therapies.
When are placebo-controlled trials ethically justifiable?: The panel provided guidelines for ensuring that placebo-controlled trials are conducted ethically, which build on the 2001 guidelines:
- When established effective therapy is not available, such as for people with primary progressive MS (PP MS*), or secondary-progressive MS (SP MS**) in which relapses are no longer occurring. The panel recommends that studies focused on a treatment’s ability to stop disease progression in people with SP MS who have relapses should still treat those relapses with established therapy.
- When participants refuse established effective therapy. Careful informed consent is essential to ensuring that the subject is aware of the MS treatments available. The panel suggests using, when possible, a health professional or informed lay person who is not a member of the research team or affiliated with the sponsor to help the subject make an autonomous decision and to maintain their understanding of that decision throughout the study. Also, they recommend counseling and re-consenting if there is a disease relapse or if an individual’s disease worsens during the study.
- When subjects have not responded to established effective therapy. If one treatment has failed, but others are available, these should be suggested to the subject before participating in a placebo-controlled study. The panel suggests using “patient-centered criterion” to determine if previous treatments have failed: Does the subject believe that this therapy was unsatisfactory, due to lack of effectiveness, side effects, intolerability, or toxicity?
- In areas where resources are restricted and established effective therapy is not readily available. Trial sponsors are increasingly conducting studies in such areas of the world. The panel recommends that, for these studies to be considered ethical, special effort be made to understand what treatments are available, as well as reimbursement policies and patient assistance programs. The sponsor should provide details about how to obtain post-clinical trial access to experimental therapies that are proven to be effective, and sponsors should make a commitment to pursue registration of any proven drug in any country in which it is tested.
- In short-term phase II proof of concept studies. There is no evidence that short-term deprivation (less than 6 months or so) of approved MS therapies can cause long-term differences in clinical outcome. If sound scientific reasons exist for doing a short-term study, the nature and rationale for the study should be carefully explained to participants.
- When the outcomes of placebo therapy do not increase serious or irreversible harm, such as clinical trials of symptomatic treatments.
Alternatives to placebo-controlled trials: Although placebo-controlled trials are the most efficient and interpretable trial design when studying effectiveness and safety of a new therapy, there are many trial design options that can avoid the use of control groups given only inactive placebo and these are discussed in the paper. One potential solution is to conduct “add-on” trials (where participants take a standard treatment plus either a new therapy or placebo version of the experimental therapy). Alternatively, “superiority” trials (where participants receive either a standard therapy or the new therapy) can be considered.
Comment: “We have only partially effective therapies for relapsing forms of MS, and no approved therapies that treat the underlying cause of progressive forms of this disease,” said John Richert, MD, executive vice president of research and clinical programs for the National MS Society. “In this light, it is vital that potential new therapies coming down the pipeline can be properly tested for their benefits and safety. This panel’s updated recommendations help ensure that testing can proceed while the individual rights of patients are protected.”
*PP MS – Primary-progressive MS, a slow but nearly continuous worsening of disease from onset.
**SP MS – Secondary-progressive MS, an initial period of relapsing-remitting MS, followed by a steadily worsening disease course with or without occasional flare-ups or minor recoveries.