Clinical Equipoise

This week’s blog will be dedicated to inform readers about ‘Clinical Equipoise’, a topic a little bit closer to my heart, as I have had a family member partake in a clinical trial.  I will commence by providing a brief definition of the term ‘Clinical Equipoise’; the basic concept is that clinicians have an ethical responsibility to provide the best possible treatment for their patients (Gravetter & Forzano, 2009).  This ‘basic concept’ seems very clear and logical, however it is very important to consider the amount of research conducted, aiming to evaluate and compare different treatment options by randomly assigning patients to different treatments.  This gives rise to an ethical dilemma, in order to evaluate and compare x amount of treatments there will need to be a baseline; which will most frequently be an existing treatment known to have little effect or placebo.  This dilemma causes researchers great difficulties as they are ethically obligated to protect participants from physical and psychological harm; ’physical harm’ in this instance would be receiving a treatment that is known to be ineffective, or simply not as effective as another preferred treatment, therefore being denied the best treatment available.  The researcher is also obligated to monitor each participant’s health for progress, decline and stability; with new untested drugs there could be dangerous side effects unknown to the researcher.

It is fundamentally important for researchers to have a point of reference to compare and evaluate the new treatment against, without another point of reference it would be impossible to decide whether the new treatment is more effective than a previous method.

The aforementioned dilemma has caused undue contention in the field, should clinical trials be harnessed by the constraints imposed by the ethical obligation to protect participants.

The solution to this dilemma is to conduct studies that only compare equally preferred treatments; this is the principle of clinical equipoise.  This means that the researcher can compare treatments when; there is honest uncertainty about which treatment is best, or when there is honest professional disagreement among experts concerning which treatment is best (Gravetter & Forzano, 2009).

The concept of equipoise in essence eliminates any studies that involve a non-treatment control group or studies that compare an active drug with a placebo (Young, 2002).

Acceptance of clinical equipoise necessarily implies that the use of placebo is unacceptable in any situation where there is an effective treatment;  preventing the use of placebo means that more patients are exposed to experimental medications that are potentially without efficacy and may have serious adverse effects.  Furthermore, examples can be found of situations in which the evaluation of potentially beneficial treatments is problematic if strict adherence to the principle of equipoise is required (Young, 2002). Young (2002) proceeded to provide an example, “under clinical trial conditions, in patients with major depressive disorder, the difference between the effects of a standard treatment and placebo is small. In the absence of a placebo arm, a new treatment could appear to be of similar effectiveness to standard treatment, yet actually be no better than a placebo. Therefore, placebo should be permitted in clearly defined circumstances, even if standard treatments exist, as long as steps are taken to minimize the risk to patients and as long as the patients understand the nature of the risks they are taking.”

Miller and Brody (2003) argue that clinical research should be treated as a separate entity to clinical therapy clinical as research is not a therapeutic activity devoted to the personal care of patients.  Instead, it is designed for answering a scientific question, with the aim of producing generalisable knowledge.  The investigator seeks to learn about disease and its treatment in groups of patients, with the ultimate aim of improving medical care.  Even though the patient may derive benefit from the treatment being evaluated, the basic goal of the activity is not personal therapy, but rather the acquisition of generally applicable scientific knowledge.  In addendum, investigators must themselves understand clearly the ways in which clinical research differs from clinical practice and ensure that potential research subjects also have a sufficient understanding of this as well (Miller & Brody, 2003).  The importance of this understanding derives from both parties possessing conflicting interests in regards to the outcomes of respective trials; patients seek therapeutic benefit whereas, investigators are more concerned with adding to the scientific knowledge about groups.

This causes a difficult and uncomfortable situation; the patient seeks effective treatment that is available but their fate is decided by their random allocation into treatment group ‘x’.

Consider this example; a family member of yours has been ill for several years with what has been thought of as an incurable illness.  A clinical trial emerges evaluating the effectiveness of what could potentially be a curative drug; your family member is recommended by their specialist for participation in this trial.  Results from the first set of trials are published and an effect has been reported.   In addition, it has been indicated that if this ‘curative’ drug does eventually come onto the market it will be very expensive, with very few health boards being in a situation where they can afford it.  With desperation setting in; the clinical trial seems to be the only way out of the illness that has tormented the family.  Then you are informed that your family member has been approved to partake in the trial, but what you are unaware of is that the treatment group that they will be randomly allocated to is the non-treatment placebo group. From this trial, a significant effect may have been reported that will be an invaluable addition to scientific research, but, your family member did not receive the curative drug and has in fact showed signs of decline.  The drug is released on the market, and your local health board will not provide funding for it, the drug is now inaccessible. 

From a Utilitarian’s viewpoint the use of a placebo in this trial and many similar to it would be fully supported, as this drug could effectively save the lives of many, by contrast, abolishing the use of placebo’s in clinical trials could harness research to the extent that this treatment and many others like it are never found.

According to Miller and Brody (2003) “a major reason to distinguish research from therapy is to underscore that clinical research has an inherent potential for exploiting research participants”.  In clinical research, the interests of investigators and patient volunteers are likely to diverge, even when the investigator acts with complete integrity.

This ethical dilemma is dominated by two incompatible positions; they are referred to as ‘the similarity position’ and the ‘difference position’.  The ‘difference position’ postulates that the ethics of clinical trials must start with the realisation that medical research and medical treatment are two distinct forms of activity, governed by different ethical principles.

Conversely, the ‘similarity position’ postulates that the ethics of clinical trials should be governed by the same moral considerations that underlie the ethics of therapeutic medicine.

Clinical equipoise is the cornerstone of the similarity position; ruling out placebo-controlled trials whenever there is a proven effective treatment for the disorder under investigation.  Despite this, Institutional Review Boards have routinely approved such placebo controlled trials.

Given that these strongly held and divergent views exist, there is an important need for (a) clearly written and consistent regulations that all researchers will comply with, whatever their own opinions, and (b) Visible and fair enforcement of the regulations.  Unfortunately, neither situation exists.

One of the cornerstones of ethical human research is the World Medical Association’s Declaration of Helsinki. Paragraph 29 of the Declaration of Helsinki states that:

“The benefits, risks, 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.”

However, the World Medical Association Council issued, in October 2001, a note of clarification on paragraph 29. This clarification states that “a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under various circumstances including: where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method.”

The World Medical Association Council’s “clarification” added further contention to the discussion, consequently confusing the situation rather than clarifying it.

 

The only transparent clarification available has been provided by The US Food and Drug Administration (FDA) policy, Guidance Document E10 Choice of Control Group and Related Issues in Clinical Trials, includes the statement that:

“In cases where an available treatment is known to prevent serious harm, such as death or irreversible morbidity in the study population, it is generally inappropriate to use a placebo control. … In other situations, where there is no serious harm, it is generally considered ethical to ask patients to participate in a placebo-controlled trial, even if they may experience discomfort as a result, provided the setting is non-coercive and patients are fully informed about available therapies and the consequences of delaying treatment.”

To conclude, there is much contention and little transparency in regards to clinical equipoise.  Researchers are ethically obligated to provide participants with the best known treatment available, if there is one.  This prohibits the use of placebos somewhat as placebos are classed as non-treatment.  However, prohibiting the use of placebo’s can harness the progression of scientific/clinical research.   Miller and Brody (2003) argue that clinical therapy and clinical research should be treated as separate entities, and researchers should be aware of this, ensuring that their participants are also aware of this.  There are two contradictory positions dominating the discussion on clinical equipoise; the similarity position and the difference position.  With two such divergent views there is a need for strict regulations and guidelines, the World Medical Association’s Declaration of Helsinki Paragraph 29 appears to be contradicted by their own clarification issued more recently in 2001.  In an attempt to end the confusion, they added to it emphasising the need for something transparent.  The US Food and Drug Administration’s (FDA) policy appears to have provided it, with clear guidelines.

 

Young, S. N. (2002)

 

Brody & Miller (2003)

http://chicago.medicine.uic.edu/UserFiles/Servers/Server_442934/File/OBGYN/Critique%20of%20clinical%20equipoise.%20hastings.%20center%20report.pdf

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