Letters to the Editor

February 1, 2005
Applied Clinical Trials

Readers respond to articles and commentaries.

Placebos and choice


In response to the "From the Editor" column about placebo-controlled trials (

ACT

, August 2004), we think that placebo use is more a tradition than an enigma. Placebo trials were the gold standard for evaluating new treatments for many years, but nowadays we need to change that point of view. Medical advances, clinical trials design development, the evolution of human subjects' protection, and ethical principles force us to rethink the idea of placebo as the best control arm.

The story from the Boston Globe is not uncommon. Who would choose the placebo over the untested drug? We feel that most of the patients enrolled in the clinical trial would have chosen the untested drug if they had been given the choice. Only those patients who decide to take part in a clinical trial due to altruistic principles would have another point of view. But, most likely even those subjects wouldn't have any predilection to only receive the placebo as treatment.

We feel that researchers should not design a clinical trial using a placebo because they are not giving their subjects the option to receive the best treatment. Regarding medical practice, patients and health professionals should look at the differences between active treatment options before they decide to choose a treatment or medical intervention. By using placebo arms as control gold standards we are comparing the treatment to an infrequent or unrealistic decision point in medical practice.

Placebo arms should be questioned in clinical trials even when there isn't an active treatment. For example, testing a new treatment with objective measurements as an endpoint when no placebo effect is expected for this variable. In these situations we should consider the best supportive care as the possible control arm.

Placebo effect can be positive by itself. Patients and physicians are looking for positive effects, even though it may be a placebo effect, to improve their health condition. The quantification and quality of the effect compared with an active treatment is more important than determining the placebo effect in the overall positive effect.

We feel that some researchers do not realize that they are exposing the placebo arm subjects to additional risks. Placebo treatment is always an experimental intervention and sometimes is an uncomfortable intervention. Negative effects in patients receiving placebo treatment have been reported frequently.1 The effects could be due to the nontreatment of disease itself or to the anticipation by subjects of adverse events that have been described to them as likely to occur in the active treatment arm. Only in those medical situations with no active treatments and with some expectation of placebo effect should placebo be used as a control arm in clinical trials. We believe that it is important to improve public opinion about clinical trials and there should be restrictions associated with placebo-controlled trials. This could lessen the effect of the guinea pig opinion of clinical trials. But, traditions are very difficult to change. Yes dear Editor, we agree with you about the woman of the story from the Boston Globe: "Unfortunately she received the placebo."

This is our personal opinion about placebo and not necessarily the official position of our center.

References
1. G. Chevtzoff and I.F. Tannock, "Placebo Effects in Oncology," J Natl Cancer Inst, 95 (1) 19-29 (2003).

Alexander Montenegro Surs,
DrPH, MSc, Prof, Project Manager
Magda Elaine Monreal Agero,
DrPH, Clinical Research Associate
National Co-ordinating Centre of Clinical Trials, Havana, Cuba

Educating to protectIn response to Toby Hindin's "From the Editor" column (ACT, September 2004), the state of the conduct of clinical research in the United States must first be placed in perspective, and the good that has evolved from the clinical trials enterprise must not be forgotten amidst the violations that have received the primary attention of the media. While one violation is one too many, a great number of investigations are conducted conscientiously and in full compliance with all applicable guidelines. Regarding legal parameters, I do not believe that it is a question of further enactment of laws, but of more educated application and beneficial enforcement guided by constant reflection on the ethics of research involving human subjects.

As an example of such an education and enforcement approach, the National Center for Research Resources, as part of the National Institutes of Health, has provided funding for approximately one full-time Research Subject Advocate (RSA) at each one of its 80 General Clinical Research Centers located throughout the United States. While the primary function of RSAs is to ensure that studies are designed and conducted safely and ethically with the protection of human subjects given highest accord, the scope of their activities are varied from individual subject attention to systems and process approaches--all viable constructs.

Moreover, this concept has spurred interest at several parent academic research institutions to employ similar approaches to the broader net of clinical investigations being conducted. The benefits truly are to educate and protect all parties involved in clinical research from subjects to coordinators to investigators, and in some instances even sponsors. It is anticipated that such enforcement will enhance the current environment without compromising the objectives of advancing medicine and improving quality of life for the citizens of this country and the world.Note: This letter does not necessarily represent the views of other advocates for research subjects nor the Society of Research Subject Advocates.

Carson R. Reider, PhD
Research Subject Advocate
General Clinical Research Center
The Ohio State University