Encephalos Journal

Ethics in multiple sclerosis
KOUTSOURAKI E., BALOYANNIS S.J.

Using placebo as a control has been the historic "gold standard" for clinical trials in MS. Placebo-controlled trials require that a proportion of patients receive inactive medication to contrast their outcomes with those treated with the experimental therapy. These trials permit 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.

There is little controversy about the need for and ethics of conducting well-designed placebo-controlled trials in forms of MS for which there is no approved therapy, such as primary-progressive MS, because doing so would not prevent patients from receiving any recognized, effective therapy for that form of disease.

An international panel met in Washington, DC, recently under the auspices of the National MS Society's International Advisory Committee on Clinical Trials in MS to discuss the ethics of conducting placebo-controlled trials in multiple sclerosis. The international gathering of 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. The last time the Society convened a summit on this topic, it resulted in publication of an influential report that has helped to guide the design of MS clinical trials since 2001. The 2001 guidelines laid out specific circumstances in which it has been considered ethical to conduct placebo-controlled trials in relapsing MS, such as when participants refuse to take or have not responded well to existing therapies. The new panel met to revisit those guidelines in light of today's clinical landscape.

Whether a trial is placebo-controlled or not, above all, a clinical trial's results must be interpretable meaning that the trial must be designed and conducted properly so that it is absolutely clear in the end whether the experimental therapy worked or not or else it would be unethical because it exposed participants to potential harm without contributing to the greater good.

It is expected that a new set of recommendations regarding the ethics of placebo controlled clinical trials and their alternatives will help to guide the evolution of MS clinical trials into the future.

Additionally, many ethical dilemmas refer to the communication between MS patients and healthcare professionals. Compassionate communication is of great value and importance, affecting not only the psychological status of the patient but also the course of the disease, acting like a "disease-modifying therapy". Listening with concern and empathy could improve MS patient's well-being, increasing overall mental health, helping to maximize acceptance and finding positive benefits from having MS.

It is worthy to ask ourselves "if I had MS I would prefer to be a member of a clinical trial or to be treated by a sensitive and compassion medical doctor?" Encephalos 2010, 47(1):18-22.

Key words: Ethics, multiple sclerosis, placebo controlled trials, stem cells transplantation.

How much to tell: an ethical dilemma

Some physicians consider that it is not always in the best interests of MS patients to be told the truth at an early stage, or even to be told the truth at all. They argue that the doctor's first duty is the relief of suffering and that to tell the truth could cause unnecessary anguish rather than be conductive to peace of mind. In support of this it is pointed out that a patient presenting early in the course of the disease, having had only two or three MS symptoms, could be free from further clinical episodes for many years or even for a life time. Other justifications for relieving patients from the burden of their prognosis are that it is impossible to predict the future with certainty and that patients are not able to understand the complexities involved.

Not knowing whether a patient really wants to face the truth can be a reason for being cautions about how much to tell. But a prolonged silence of these grounds can sometimes result from the reasonable doctor's optimism on the further clinical course of the disease.

Alternatively a gloomy picture of the future may have been by doctors with an over-pessimistic view of the disease based on treating sometimes severely disabled patients. But many people with MS live normal lives and may have little or no disability even after many years.

A few MS patients have told me they resented being given their diagnosis early because they had altered family and carrier plans unnecessarily in the light of subsequent events. In these cases the failure could have been in how they were told rather than how much.

In my experience the substantial number of MS patients have wanted to know the nature of their disease as early as possible. They have been keen to discover all they could about the disease to enable them to make their own decisions about the future. Many have felt they had the right to know about their illness and to participate in their own treatment.

The ethics of placebo controls in MS clinical trials

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS.

The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures.

Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

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. There is little controversy about the need for and ethics of conducting well-designed placebo controlled trials in forms of MS for which there is no approved therapy, such as primary progressive MS, because doing so would not prevent patients from receiving any recognized, effective therapy for that form of disease.

The ethical concerns are greater when there are approved disease-modifying therapies, such as in relapsing forms of MS.

Design issues

For trials in relapsing forms of MS, comparing a new drug to inactive placebo allows a study to proceed with a relatively small number of subjects, which can ease recruitment and reduce costs, yet leaves those on placebo possibly vulnerable to the immune attacks and relapses that currently available therapies can partially prevent.

In MS, there are many trial design options that can avoid the use of control groups given only inactive placebo. 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.

In a relatively infrequent disease like MS, recruiting the large numbers of participants needed for such trials is difficult. In addition, safety concerns can arise because of the unknown impact on adverse events of adding therapies together in add-on trials and of the unknown safety profile of a new agent to which a large number of people will be exposed in a superiority trial.

Whether a trial is placebo-controlled or not, above all, a clinical trial's results must be interpretable - meaning that the trial must be designed and conducted properly so that it is absolutely clear in the end whether the experimental therapy worked or not - or else it would be unethical because it exposed participants to potential harm without contributing to the greater good.

Stem cell transplantation in multiple sclerosis: safety and ethics

Stem cell therapy is considered a promising strategy aiming at neuronal and glial cell replacement or neuroprotection in neurological diseases affecting the brain and spinal cord. Multiple Sclerosis (MS), characterized by inflammation-induced destruction of the myelin sheath surrounding axons leading to conduction deficits and variability of clinical signs, is not an exception. MS is considered an autoimmune disease and, in the last few years, an intense immunodepletion followed by autologous hematopoietic-stem-cell transplant (HSCT) is being assessed as potential therapeutical strategy for severe patients unresponsive to the immunomodulatory and immunosuppressive treatment.

Partially supported by evidence in animal models and by anecdotal reports on the beneficial effects on MS patients with concomitant malignant diseases, HSCT programs for MS have been initiated worldwide and follow-up data are accumulating. A Consensus Meeting has been held in Milano (1998) providing a document that defined criteria for patient selection, transplantation procedures, and outcome evaluations. Nowadays the high number of patients already treated allows us to draw initial conclusions related to clinical efficacy. After careful monitoring of the available data and improvement of the procedure, safety seems not to be anymore an issue.

Ethics of HSCT deserve, on the contrary, a profound evaluation: the procedure is a multistep process with manifold options, each step with different ethical implications. Even more difficult appears the definition of the MS patient selection criteria for HSCT. The informed consensus needs to be exhaustive for the full comprehension of a complex procedure. In conclusion, although HSCT is today an established therapeutical option for MS patients, safety and ethical issues need to be further clarified.

Conclusions

We must keep in mind that compassionate communication is of great value and importance, affecting not only the psychological status of the patient but also the course of the disease, acting like a "disease-modifying therapy". Listening with concern and compassion could improve MS patient's well-being, increasing overall mental health, helping to maximize acceptance and finding positive benefits from having MS.

A moral question for the physician is whether to do what he thinks is right when this differs from the patient's wishes. It is difficult for the doctor to be sure that he accurately knows what the patient really wants. Although there are no simple answers to these questions they emphasize a need for the doctor not just to understand the patient but also to be aware of his own feelings and attitudes.

The physician must be prepared to consider what the truth could mean for a particular patient and it is surely right to respect a patient's need to make his own decisions. The doctor's prime task must be to provide the patient with the information and support they require to live with the demands of an uncertain future.

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