Sham Surgery Opinion Survey – The Results Are In

The Survey Questions

Did you know that some clinical trials use sham surgery (1) as a placebo control?  (Y or N)

Is the scientific information gained  by such studies worth the risk to volunteers who receive the sham surgery? (Y or N)

Would you volunteer for a trial knowing you could receive sham brain surgery? (Y or N)

What guarantees from scientists and trial sponsors would you expect to make the risk worthwhile? (open ended)

Any other comments? (open-ended)

The Survey as posted during August 2007 (click here to go to this section of the page)

The Results

Most of the respondents (74%) said they are aware of the use of sham surgery in clinical trials for PD.  About 36%  think the information gained by these type of studies are worth the risk to the volunteers who received sham surgery, and  38%  said they would be willing to volunteer for a trial that utilized sham surgery.

Respondents stated they would be more likely to participate in such a trial if they could be guaranteed:

• Future treatment if the trial proved successful
• Full coverage of  medical expenses due to adverse effects from the treatment or surgery

They also want full disclosure by the trial sponsor and investigators about the risks involved, the percentage of participants who will receive sham surgeries, and the reasons why it is considered necessary as a placebo control. Respondents also cited a lack of trust in drug companies and scientists.  Responses to the open-ended questions are included at the end of this article.

We received 35 replies to the survey during the month of August 2007.  The survey was publicized on the Parkinson Pipeline Project web site, the Neurotalk Forum and the Parkinson Information Exchange Network (Parkinsn List).

Discussion

Although this survey involved a small sample and was non-scientific, it does provide a range of opinions about sham surgery among a group of PWP who are highly educated about the disease. Many of them are active in PD organizations and advocacy. They are also more aware of and more likely to participate in clinical trials than the general population of PWP.

Clinical trial sponsors should seriously consider their concerns and opinions, since the future likely holds a growing number of clinical trials involving experimental brain surgery for PD and the need for many more volunteers. Larger, scientific studies of patient viewpoints are needed.

The Parkinson Pipeline Project also 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. For now, 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. Larger, scientific studies of patient viewpoints are needed. (2)

Notes: (1)  Survey definition of sham surgery: “As a placebo control, sham surgery means there will be some patients that will undergo anesthesia, IV solutions, and surgical prep to undergo anesthesia, will have to be placed on IV solutions, and be surgically prepped, but will not receive the treatment under trial. No one other than the neurosurgeon will know who receives the sham surgery.” (2)  Karl Kieburtz of the University of Rochester is leading a study on “Ethics of Sham Surgery Controls to Test Novel Parkinson's Disease Intervention.” They will interview “participants of PD clinical trials that involve sham surgery controls…to  assess the potential for the therapeutic misconception by describing why and how PD patients make their decisions regarding participation in sham surgery controlled studies.”  They were awarded a Michael J Fox Foundation 2007 Rapid Response  Innovation Award for this study. The grant abstract is available here.

Responses to the open-ended questions are included at the end of this article

Did you know that some clinical trials use sham surgery as a placebo control?

Yes: 26

No: 9

Is the scientific information gained by such studies worth the risk to volunteers who receive the sham surgery?

Yes: 12

No: 21

Would you volunteer for a trial knowing you could receive sham brain surgery?

Yes: 13

No: 21

There was also an open-ended question: What guarantees from scientists and trial sponsors would you expect to make the risk worthwhile?

Grouped by topic the most frequent responses  included:

There are no guarantees that would make it worthwhile:  7

Guaranteed to get the treatment if it proves effective:  7

Full disclosure; the risks are clearly explained; know odds of getting sham:  5

Guarantee sponsor will pay for all medical expenses if adverse effects occur:  4

Accurate reporting of results by an independent monitor 1

Animal trials should first determine if any long term risk:  1

Guarantee no adverse effects: 1

Explain why there is no other way of doing the trial: 1

Full comments follow:

Question: What guarantees from scientists and trial sponsors would you expect to make the risk worthwhile?

• THERE ISN'T A GUARANTEE THAT WOULD MAKE IT WORTHWHILE.   I WAS GIVEN THE OPPORTUNITY OF PARTICIPATING IN THE CERE GENE THERAPY PHASE 2 TRIAL AND WOULD HAVE PROBABLY PARTICIPATED IF I KNEW I WAS NOT GOING TO HAVE TO RISK THE SURGERY FOR NOTHING OR WAIT AND DO IT AGAIN AT A LATER DATE.

• I cannot justify the sham surgery under any circumstances.

• From the above information given can the scientists and trial sponsors give any guarantees at all?

• Guaranteed expenses for patients care for the rest of their life.

• It needs to be made really clear to the patient that they may be getting sham surgery. Most informed-consent documentation I have seen is pretty pro forma.  In this case, there are real risks, so it should be made really clear. I would suggest that someone other than the investigators deal with informed consent, perhaps someone specializing in medical ethics.

• If I were randomized for sham surgery, guarantee I, the patient, would receive all the follow-up care needed cost free and would be first in line for real surgery, if proven effective.

• The only guarantee I would expect is accurate reporting preferably supported by independent monitor.

• To be the beneficiary of the real surgery if trial is successful. To be sure the risks and benefits are clearly delineated and understood by the potential subject.

• A guarantee that if the data results are favorable towards the therapy that I would be able to have the "real" thing at the end of the phase I have participated in.

• Guaranteed...no negative results, e.g., brain damage...poor and even deadly response to anesthesia, etc. It seems that these would be absolutely impossible guarantees.

• Full knowledge and agree to pay for alternative

• I don't agree with it at all.

• If treatment is effective, the opportunity to receive treatment for those who have the sham surgery...and continuing treatment for those who received the real thing. Of course, post Amgen, who will have faith in such guarantees?

• Full disclosure of known risks, plus a written commitment to provide full treatment at no cost in the event of an adverse experience following surgery

• I would expect a guarantee that I would receive the real treatment if it were successful in other patients

• It would help if the animal trials could convincingly state what the long-term effects would be.

• People must know what the odds are for receiving the sham surgery.  For a disease that ruins your Q of L, some people will try anything but we must be honest in that probability assessment.

• The statistical proof is not available in another way.  I am no expert but can’t we demonstrate that something is helpful just by a larger sample size or is a control group always required?  Can’t we pair people as close as possible and not have sham? 

• I don't think it is possible to make the risk worthwhile. I think the decision to have brain surgery is difficult enough in itself without the possibility of receiving "sham surgery".

• I would want the original surgery done as soon as possible, and hope it works.

• Opportunity to get real surgery if desired in the future.

• If I received the sham and could be assured that if the study was a success, I could then get the real surgery. 

• I do not believe guarantees can be offered.  Surgery, sham or not, offers too many risks to be taken lightly.

• I would expect an especially high assurance of medical/financial support from trial sponsors for any adverse effects even possibly related to the surgery.

OTHER COMMENTS

• It is one thing to have clinical trials where the placebo is in the form of a pill, patch, or injection-the latter considered minimally invasive, but "sham" neurosurgery? Scientific information gained? This sound's like something out of Nazi Germany.

• Let them try this on a group of their scientist first.

• I have seen references to non-placebo designs.  If someone could summarize that literature, it would be helpful. Perhaps for this and other risky treatments, there could be an intermediate phase between II and III.  This would involve a small number of human subjects and would be open label but would be designed to provide good evidence of efficacy, before going to the full placebo-controlled trial. At this point, I do not see any way to eliminate placebo-controlled trials altogether.

• I'm early stage PWP--no meds but taking CoQ10.  I've educated myself on the eventual outcome of this disease and I would try most any drug/surgery trial that shows potential to control/stop/prevent this hideous disease.

• Designate fast track based on risk of harm by drug.  Harm by surgery should be considered separately.  It’s the drug that’s new.  Fast track should not take 5 years for 68 participants.

• I have been a subject in the Olanow fetal transplant study and developed the runaway dyskinesia which was an untoward result of the real surgery DBS controlled that though. I have no regrets about having participated.

• There are alternatives to double blind trials, they are actually becoming quite common for diseases like cancer where it would be unethical to give a patient a placebo and let the patient die to prove that a new medication is effective.  The studies aren't as simple, but these could and should be applied to Parkinson’s surgeries as well.

• Anyone willing to participate in "sham surgery" MUST first know the possible negative outcome...then, only, give consent. Iwould think that one would have to be SO   desperate to even consider "sham surgery".

• It is not clear how much negative effect the real surgical effect of "sham" surgery introduces.  it is a "placebo" that is not neutral and thus not a placebo, but rather a factor of unknown effect.

• Disgraceful using PWP who are desperate or low income earners that will try it. Preying on their vulnerability. DBS is miraculous and no humans were given sham surgery for that.

• Having had brain surgery twice (DBS) I don't favor it as a "sham" for trials or in the future as any kind of routine treatment for PD or anything else. It is too much to ask of anyone.  Even though PD is   "'in your head" it isn't subject to a placebo effect anyway, in my opinion.

• I personally would defer participation in a trial involving sham surgery until my condition worsens considerably.

• I would consider volunteering for a clinical trial that used sham surgery if I were guaranteed that I would receive the full treatment if the study were successful.

• I would also expect the trial sponsors to pay for medical treatment made necessary by my participation in the trial.>

• I'm ashamed to say that I am not willing to participate in drug or surgery trials. Somebody has to go first.  My feeble excuse is that although I have many caring friends and family, I live independently by myself. I have no caregiver nor enough resources to hire one.  With so many unknowns, it's likely that kind of care would be needed for people participating in trials.

• Are we being truthful when we say the placebo effect might be a year?

• I don't believe sham surgery is equivalent to receiving a placebo.

• I think sticking with animals in such trials, not humans would be best.

• Perhaps my position on accepting sham surgery would depend on my level of  desperation

• It is impossible for me to adequately express my gratitude to those subjects who have participated in the trials involving control sham surgery.  They are my heroes!

Survey Results Last updated 9/06/07

The Survey as posted during August 2007:

Survey on SHAM SURGERY in Parkinson’s clinical research. What do you think?
 

As more Parkinson's  treatments involving surgery move into phase II clinical trials, (such as CERE120 and GAD gene therapies and Spheramine cell therapy), we can expect increased use of sham surgery  in clinical trial designs. 

As a placebo control, sham surgery means there will be some patients that will undergo anesthesia, IV solutions, and surgical prep to undergo anesthesia, will have to be placed on IV solutions, and be surgically prepped, but will not receive the treatment under trial. No one other than the neurosurgeon will know who receives the sham surgery.

What is your view of the use of sham brain surgery in Parkinson’s research? Please read the following excerpt from our recently published article on research ethics and think about whether you support the practice of sham surgery in clinical trials. Then tell us your opinion by answering the short questionnaire below.

The following excerpt written by: Perry Cohen, Linda Herman, Sheryl Jedlinski, Peggy Willocks, Paula Wittekind, is from Ethical Issues in Clinical Neuroscience Research: A Patient’s Perspective. Neurotherapeutics 4 (July 2007), 537-544.

Sham Controls …Scientists’ Views

Double-blind, placebo-controlled trials are considered to be the gold standard in clinical research. Many investigators cite the Freed fetal cell tissue transplant study for advanced Parkinson’s disease and subsequent follow-up studies by McCrae and others as evidence that the placebo effect may be especially strong and long lasting—as much as a year or more—in surgical treatments for Parkinson’s patients.

In the initial study, human fetal cell tissue was implanted into the brains of patients in the treatment group; for the placebo group, burr holes were drilled in their skulls but nothing was implanted. Both groups were given anesthesia and intravenous antibiotics. Researchers argued that the risks associated with the surgery were reasonable in relation to the possible benefits from the outcome of the study.

Clinical researchers emphasize the importance of placebo- controlled trials, including sham surgeries, for evaluation of promising future treatments such as gene therapy and cell implantation. Of 103 investigator members of the Parkinson’s Study Group10 who responded to an on-line survey in 2004, a vast majority believe that sham control design is scientifically superior to an open control design and that it is ethically permissible. Specifically,

• 90% said drilling burr holes in the heads of sham control group members is justified.
• 22% said penetration of brain tissue in a control group member is justified if it leads to a definite answer.

PATIENT ADVOCATE VIEWS

Patient advocates ask how, in good conscience, we can sell our peers on placebo controls, and sham surgery in particular. The regulatory approval process does not require placebo-controlled trials. For example, DBS (deep brain stimulation) was approved by FDA with no placebo control.

Previous studies citing observed improvements in PWP following sham surgery overlook the fact that this so-called placebo consisted of a range of interventions that put patients at significant risk. Sham surgery is not a sugar pill. Patients incur not only the risks of having a hole drilled in their heads, but also the significant risks associated with undergoing anesthesia, as well as the emotional trauma of preparing oneself for experimental brain surgery with no expectation that these interventions will ease their symptoms.

Increasing risk for trial participants is not ethically justified unless, before agreement to participate is secured, the supporting evidence is clearly spelled out as part of an informed consent process that weighs individual risk– benefit choices. In a patient-centered clinical trial system, the burden of proof is on the researcher to show that the value of the data to be gained from the placebo group outweighs the risks to the participant. A study would have to provide evidence for prolonged positive effects from the sham intervention and show a difference between this placebo surgery and other possible controls, such as no treatment groups or historical controls. ..

According to one researcher, “There’s literature representing the opinion of neurologists and ethicists but little to formally represent patient opinions. Before we inject the ‘putative curative stuff,’ we should assess patients’ willingness to participate, knowing they may receive a potentially injurious agent.”

Click here to read the full article

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