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Report on New Survey on SHAM SURGERY in Parkinson’s Clinical Research
June 16, 2010
2007 Survey Results
Introduction
As more Parkinson’s treatments involving surgery, (such as gene therapies and growth factors) move into phase II and III clinical trials, we can expect increased use of sham surgery as a placebo control in clinical trial designs. However, there continues to be controversy about its use among researchers, regulatory agencies, and doctors, who consider placebo controlled clinical trials to be the gold standard, and clinical trial participants, who might become more hesitant about volunteering for trials that involve drilling into their skulls and possibly entering their brain tissue.
Recognizing the need for a thorough review of the ethical, scientific, and medical issues; the NIH will be conducting a 2-day conference on June 30-July 1, 2010, “Sham Neurosurgical Procedures in Clinical Trials for Neurodegenerative Diseases: Scientific and Ethical Considerations.“ There have been few studies focusing on patients' perceptions of sham surgery (1), and many questions remain. In 2007, the Parkinson Pipeline Project (PPP) conducted an informal survey on the views of People with Parkinson's (PWP) on sham surgery (2), and in June 2010, we conducted an updated survey.
Both the 2007 survey, and the current one were small and non-scientific. However they both provide a range of opinions about sham surgery from a sub group of PWP who are educated about their disease and are reading, researching, communicating and sharing information online. Many of them are active in PD organizations and advocacy. Fifty percent of those who responded to this survey have participated in clinical trials, while less than 1 % of the general population of PWP have done so.
How were survey participants recruited?
The survey was posted during June 2010 on a number of Parkinson’s online discussion groups and mailing lists, including: The Parkinson List (PIEN), Neurotalk, The Clinical Trial Learning Institute (PDF) graduates (about 25 % of the respondents were graduates of this program), and the Parkinson Pipeline Project, Young Onset Forum of NPF, and the Patients Like Me PD forum.
Who participated in this survey?
Thirty-five PWPs responded during the two weeks allotted for the survey. Their ages ranged from 43 to 78 years. The average age was 61.4 There were about equal number of men and women. They ranged from 1 – 25 years since diagnosis, the average being 8.5 years.
Significantly over half ( 51.4 %) of these respondents reported that they have participated in PD clinical trials (2 were in surgical and 16 were in medical trials), while the national participation rate is estimated to be less than one percent . The perceptions and opinions of these respondents should be of interest to all stakeholders in clinical trial and drug development process.
What is sham surgery?
For the purposes of this survey, as a placebo control, sham surgery was described as including the following elements:
“A control group of randomly selected trial participants will be surgically prepped, be placed on IV solutions, undergo anesthesia and have burr holes drilled into their skulls and possibly enter into brain tissue, but they will not receive the experimental therapy.
They may also receive immunosuppressants and/or antibiotics following the sham surgery.
All surgical procedures and possible risks must be explained to and agreed to by the patient as part of the informed consent process.
These trials are usually double-blinded – neither the patient nor the trial staff, except for the neurosurgeon knows if they received treatment or a sham procedure. “
Alternative trial designs are being developed, but are not yet widely accepted by the consensus of North American scientists and the FDA.
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The Survey Questions and Responses
Survey of PWP on Sham Surgery in Parkinson’s Clinical Research (2010 update) and comparison with 2007 responses:
“Some questions will be asked twice. Answer the first in regard to sham surgery that involves drilling into the skull, but does not penetrate any brain tissue. Answer the second in regard to sham surgery that involves drilling into the skull and penetrating the
brain tissue (e.g. inserting a brain catheter; needle passes through the brain, implanting a delivery device, such as a pump, etc) (3)
1. Before taking this survey, did you know that some clinical trials use sham
surgery as a placebo control? (Y or N)
YES 29 (83%) NO 6 (17%)
In 2007 survey 74% answered YES
2. Is the scientific information gained by clinical trials worth any risk to trial
participants who receive sham surgery (burr holes drilled into the skull only ) ?
(Y or N)
YES: 8 (23%) NO 26 ( 74%) NA 1 (3%)
In 2007 survey 34% answered Yes to any type of sham surgery
3. Is the scientific information gained by clinical trials worth any risk to trial participants who receive sham surgery (burr holes drilled into the skull and brain tissue penetrated? (Y or N)
YES: 1 (3 %) NO: 31 (88%) NA 3 (9%)
In 2007 survey 34% answered Yes – scientific information gained was worth the risk to volunteers who receive sham surgery
4. Would you volunteer for a trial knowing you could receive sham brain surgery in which your skull would be drilled into? (Y or N)
YES: 6 (17%) NO: 29 (83%)
In 2007 survey 37% said they would volunteer for trial that involved sham surgery (type not specified)
5. Would you volunteer for a trial knowing you could receive sham brain surgery in which your skull would be drilled into and your brain tissue penetrated? (Y or N)
YES: 1 (3 %) NO: 34 ( 97%)
In 2007 survey 37% said they would volunteer for trial that involved sham surgery (type not specified)
The remaining 2 questions were open-ended.
6. Are there any guarantees from scientists and trial sponsors that would make the risk acceptable to you? Open ended question.
Responses - The most requested guarantees were :
Guarantee that they would receive the treatment once trial was over if it proved to be successful
Any medical expenses due to adverse events caused by the treatment would be covered.
More transparency. Patients should be given more information about the trial and the treatment, and there should be more patient input into the decision-making process.
In their own words
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“Maybe if they took over all my health-care costs forever and if I would receive the actual surgery the instant it was shown to be safe and effective.”
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"Proof of outcome”
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“Given the potential risks associated with neurosurgery, there are NO guarantees that would induce me to participate in a clinical trial in which "sham surgical" procedures are utilized. “
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“Guarantee of honesty. For me to consider it, I would need access to data such as history of complications and cure rate. In addition, each of these studies should have several patient advocates that would raise issues that the patient may overlook. In other words, the patient must have the same level of information AND equivalent sophistication in order to make a truly informed decision. Of course, the study must guarantee that any needed medical care will be provided free of charge.”
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“If I was desperate and they guaranteed the real treatment.”
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“If the surgery on the actual patients was successful that I would be eligible for free surgery after the trial was completed.”
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“Yes, if the real surgery were successful that the surgery would be performed on me. "
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“If we had better diagnostic biomarkers, and knew more about the chemical changes that occur in brain surgery, I would feel better about the risks. More patient input into the decision-making process would help, also..”
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“NO, BECAUSE I DON'T BELIEVE THEY KNOW ENOUGH TO GIVE PROPER GUARANTEES”
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“YES, pay for my care and support indefinitely IF something went wrong during surgery, such as a stroke, bleeding on the brain, etc. OR after the surgery IF the device implant (be it real or sham) caused any problems.”
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7. Do you have any other comments? (open ended question)
The most common responses were:
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Disbelief that sham surgery is necessary – “There must be another way.”
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Only the most “desperate” patients would agree to sham surgery.
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We do not know enough about the placebo effect to justify use of sham surgery.
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It is “unethical..”
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In their own words
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“Surely there are other models for trials of new surgeries. Can’t the surgery be compared to no surgery?”
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“It is unethical to submit trial participants to sham brain surgery, there are other means to obtain reliable data to support the results of clinical trials, better models for these need to be developed. Ignoring patients feelings on this inevitably will lead to a low uptake by potential participants. In order for studies to be larger and give clearer results this issue needs to be addressed.”
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“Surely there must be other methods of determining whether an experimental treatment results in authentic positive effects or placebo effects. Or until these exist, give all trial patients the experimental treatment and record the markers for the end point determinations. Once a method to separate placebo effect from true clinical effect, then a differentiation can occur. Just what do other countries utilize? I cannot believe sham neurosurgery is wide spread in clinical trials thru out the rest of the world. “
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“Any physician who plans a clinical trial should aggressively counter an FDA suggestion that the only way that the study can be "adequate and well-controlled" is through the use of sham surgery as a control. See 21CFR314.126”
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There are no circumstances under which sham surgery is esthetically (ethically(?) acceptable. The idea of anyone giving informed consent is ludicrous. It would only out of desperation that anyone would participate in experimental brain surgery.”
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“We are humans -the placebo effect in humans is called "Faith"and faith is a belief in an honorable G-d”
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“APPEARS TO NOT FOLLOW INSTITUTIONAL REVIEW BOARD STANDARDS NOR BELMONT REPORT FOR ETHICAL RESEARCH”
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“As my condition progresses I might feel more open to sham surgery where the skull is penetrated, but not the brain.”
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“You volunteer for a trial knowing you could receive sham brain surgery in which your skull would be drilled into? (Y or N) no but I would not volunteer for a trial for an untested compound, either - not worth the risk at this point - perhaps if I were more desperate, I would feel differently.”
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“Answers will depend on severity of disease”
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“As my condition progresses I might feel more open to sham surgery where the skull is penetrated, but not the brain.”
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“I had DBS surgery in 2007 and at that time the surgery was worth the risk to me because "I would have rather died than continued to live the 'shut in' life I was living. Fortunately for me... the surgery gave me my life back! I suppose if, or when, I reach that point again I would be willing to volunteer for brain surgery, be it sham or the real thing! “
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“More research is needed on placebo effects to justify sham BEFORE I would consider participating in a sham trial. The burden of proof is on the scientists not on the patients.”
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“.IF THE DESIGN SUCKS … AND RESULTS ARE INCONCLUSIVE BECAUSE OF THAT, THEN NO. Or, if they are studying something we already know, like the recent DBS trial that showed that dbs is effective in advanced (read: at the end of the levodopa road) PD, then no (I know that trial had no sham arm, it is just an example that fit my needs but happened to involve brain surgery) - difficult to answer yes or no, in other words.”
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“There is too much ambiguity about positively diagnosing PD to risk sham surgery. Also, science has been working with a dopamine replacement model for over 40 years. Maybe we have been totally wrong in our approach.
In my opinion, PD is both a movement and a mood disorder with the same neural pathways used. This could be inflating the already inflated placebo effect even more and longer than we think. It is time for a new model to help solve this mystery. “
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“I AM ALWAYS HUMBLED BY THE COURAGE OF FOLKS WHO PARTICIPATE IN THESE TRIALS.”
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“WHY NOT ASK THE SCIENTISTS AND THE FDA WHO ARE NOT READY TO ACCEPT ALTERNATIVES TO TAKE THE SURVEY”
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“ I would say as comment: Let’s enjoy the placebo effect and not risk lives just to measure it.”
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Conclusions and recommendations
The acceptance of sham surgery as a placebo control and willingness to participate in such a trial has decreased among survey respondents since 2007, as shown by questions 2-5.
It is instructive to compare the results of the 2007 and 2010 surveys and see what has changed and what hasn’t over the last three years. Although more people are aware of its use in 2010, the current survey respondents are less likely to believe its use is worth the risks to individual PWP. Almost unanimously they replied that they would not volunteer for a trial that utilizes sham surgery (37 % would volunteer in 2007, but only 17 % and 2 % in 2010. )
Compare these results to a 2005 (we are not aware of a more recent survey) online survey of 103 investigator members of the Parkinson’s Study Group. Ninety percent said drilling burr holes in the heads of sham control group members is justified. Twenty-two percent said penetration of brain tissue in a control group member is justified if it leads to a definite answer. (4) Yet only 1 out of 35 our survey respondents would agree to participating in such a study, and based on the comments we received, that patient is likely to agree because they believe they have run out of options and are desperate for any treatment that might help them
There appears to be a huge disconnect between how scientists perceive patients’ opinions on the issue of sham surgery and what patients really think. We need to reconnect through two-way communication and education.
It is also interesting to read patients comments from 3 years ago, and realize they haven’t changed very much. It appears few of the recommendations were addressed, and little discussion of the issues has taken place.
A number of the comments dealt with “therapeutic misconception” This is a commonly held belief among scientists and some medical ethicists that patients should not volunteer for trials believing they will benefit medically from the experimental treatment. Yet many of our respondents stated they wanted to be guaranteed they would receive the experimental treatment, as soon as the blind is lifted. Considering the many failed and terminated trials in the last 3 years those assigned to the control groups, who received sham surgery are unlikely to ever get the real thing
Clinical trial participants are told that patients should volunteer for the good of future generations only and not to expect medical benefits for themselves . These researchers don’t seem to realize how desperate many PWP REALLY ARE, even the most altruistic participant still hopes for some therapeutic effect. Indeed a number of respondents commented that they would only consider joining a sham trial if they had reached the point of desperation. There appears to be a huge chasm between researchers and patients on this issue . We believe it can only be bridged by honest and equal communication between all stakeholders. Though the opportunity for patient feedback is limited in the upcoming NIH workshop, we hope this workshop will open up a much-needed dialogue.
Our recommendations are essentially the same as in the 2007 survey report.
The Parkinson Pipeline Project believes that the use of sham surgery in PD clinical trials raises safety and ethical issues that should be investigated further, and that patient input should be sought and considered.
Larger, scientific studies of patient viewpoints are needed.
Better understanding of the placebo effect in PD is crucial.
As part of the informed consent process, the researchers and sponsors should explain how the value of the data gained from the placebo group outweighs the risks to the participants. They should provide evidence that alternative study designs were considered and explain why they chose to use sham surgery.
The Parkinson Pipeline Project thanks all the PWP who participated in this survey and especially thanks all who seek to acelerate PD research progress by volunteering for clinical trials.
NOTES:
(1) Frank, SA, (et al). Ethics of Sham Surgery: Perspective of Patients. Movement disorders. 23, 1, 2008, 63-68.
(2) The 2007 survey with results available online at: http://www.pdpipeline.org/whatsnew/shamsur_survey.htm
(3) In the 2007 survey the types of surgery (burr holes drilled in skull only or brain penetrated).were not asked or answered separately as they were in 2010
(4) Kim SY, Frank S, Holloway R, Zimmerman C, Wilson R, Kieburtz K. Science and ethics of sham surgery: a survey of Parkinson disease clinical researchers. Archives of Neurology, 2005;62:1357–1360.
Linda Herman, on behalf of
Parkinson Pipeline Project
June 2010
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