Friday, December 23, 2011

Sham Surgery: All Options Should be on the Table

The issue of whether or not a sham brain surgery is necessary for the research of Parkinson’s disease is complicated. Following several decades, different treatments for Parkinson’s disease have been developed, such as cell implantation, fetal nerve-cell transplantation or gene therapy. There was some common point that the radical or significant effect on the improvements of motor disability or balance control was found during the phase I trial; however, during the phase II trial, the treatment effect did not precede that in the sham-surgery control group. In an ethical point of view, is it ethical to easily and immaturely shift studies failed in the phase II trial without regard to the potential values to patients? Besides, due to the shortage of funding resource, fewer and fewer research groups could afford the expensive sham-surgery which is also too risky to find enough subjects of the control group to compare with the experimental group. Therefore, increasing numbers of scientists started to argue about whether the sham-surgery is really necessary.

An article “Experimental therapies for Parkinson's disease: Why fake it?” published on Nature on August 11, 2011 started to discuss the dilemma, the conditions that scientists currently face, and the suggestions with that scientists provided [1]. The story began with an experiment called Spheramine, developed by a biotechnology company, Titan Pharmaceuticals. In this experiment, Peggy Willocks was the second recruited subject in the phase I trial who received an implantation of human retinal epithelial cells into her brain in August 2000, and the scientists hoped that the implanted cells would produce L-dopa, which could reduce the symptoms related to motor disabilities, such as dyskinesia or poor balance control. After 9 months, a great improvement in her balance control impressed the scientists, and similarly, several subjects in the phase I trial showed moderate improvements in motor disabilities. This, however, should be the exciting results to scientists and most Parkinson’s disease patients, but disappointingly the study was shelved and no longer operated until ten years later due to the results in phase II showing that it was no more effective than placebo. With regard to this “common” situation, Dr. Roger Barker at the University of Cambridge argued against the placebo-controlled study in terms of the costs, risks of sham surgery to healthy people, and the potential damage of the placebo-controlled study to promising treatments.

The sham-surgery as a placebo-controlled procedure is used to eliminate the false-positive results in the research of Parkinson’s disease. An experiment in 1987 attempted to use adrenal gland cells to produce dopamine, and this treatment was claimed to successfully produce positive results [2], and so did two other studies using Glial cell line-derived neurotrophic factor (GDNF) transplants [3] and retinal epithelial cell implantation [4]. However, later studies showed that the aforementioned positive results were not reproducible and some studies even pointed out that the treatment effects were no more than placebo effects. Until now, the sham-surgery in Parkinson’s disease is defensible and reliable to reduce confounding factors, such as patient’s expectation, to cause false-positive effects. Dr. Jon Stoessl at the University of British Columbia provided supportive evidence that patient’s expectation was strongly influenced by their functional improvements [5]. Therefore, the supporters of the sham surgery claimed that the placebo-controlled procedure offered an objective measurement to prevent patient’s expectation from sheltering the treatment effects.

Although the sham surgery in the research of Parkinson’s disease is widely accepted, some new points of view that the sham surgery is unnecessary are generated. First of all, the approval of the sham surgery is rarely acceptable in some regions, such as in Europe, which means that whether to operate the sham surgery depends on the region’s scientific policies, and therefore the sham surgery cannot become accepted and apply to all clinical research. Second, the lack of treatment efficacy in the open-labeled study as compared with the placebo-controlled study may result from the short-period follow-up (usually less than one year) due to inevitable difficulties, which indicates that the treatments should take more than one year to produce effects on the “clinical” improvements. As time goes by, the placebo effect (patient’s expectation) becomes weaker and the value of treatments becomes more evident. Finally, a more central concept is brought up that whether scientists should be concerned about patient’s expectations, and whether their expectations can be tolerated and can even be useful in research although that would affect the baseline of the objective measurement in scientific research. Dr. Perry Cohen mentions that because the failure in phase II trial of GDNF caused safety concerns, the further research was shelved for almost 6 years. Due to the safety concerns in the scientific studies, is it unethical to process an open-labeled study and allow patients to know their treatment protocols? A clinical case of Parkinson’s disease showed that the physical conditions can be dramatically influenced by the psychological aspects of self-belief. Although it is hard to quantify the psychological contributions, the medical treatments should accompany with self-expectation, which would cause further treatment efficacy.

Whether the sham surgery is needed is still under debate, but the aim of the sham surgery is to eliminate false positive effects. However, it is inevitable to remove the false negative effects. The most important thing to patients is hope, which means not to discard a potential treatment so easily due to the failure in the phase II trial. In the scientific field, a clinical research without a placebo-controlled group will easily receive dramatic critique instead of been recognized by the contributions. However, like patients will say “false negative is better than false positive.” All patients want are the improvements of their function in the future. 

--Ian Chou
Neuroscience Graduate Program 


Want to cite this post?
Chou, I. (2011). Sham Surgery: All Options Should be on the Table. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2011/12/sham-surgery-all-options-should-be-on.html


References
  1. Katsnelson, A., Experimental therapies for Parkinson's disease: Why fake it? Nature, 2011. 476(7359): p. 142-4.
  2. Madrazo, I., et al., Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson's disease. N Engl J Med, 1987. 316(14): p. 831-4.
  3. Lang, A.E., et al., Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol, 2006. 59(3): p. 459-66.
  4. Stover, N.P. and R.L. Watts, Spheramine for treatment of Parkinson's disease. Neurotherapeutics, 2008. 5(2): p. 252-9.
  5. McRae, C., et al., Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry, 2004. 61(4): p. 412-20.

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