I too had brain surgery...in June 2007. I was not told that I would experience facial swelling.

My swelling was bad enough that even 10 days late is was rather significant. It is my understand from my family that I was pretty much unrecognizable immediately after the surgery.

I understand that this is an indication of invasion into the brain. My Principal Investigator had told me that he and the Trial Coordinator were not allowed to visit me until our first post-surgery trial evaluation. I did not ask at the time, but I can only assume that this is due to the telling factor of the facial swelling...that the brain had been invaded, hence the real surgery had taken place....not the sham surgery.

Or could the swelling be due to the frame that is placed on the head during brain surgery. Maybe a DBS patient can comment on this. I tried to search the Internet for the "post-surgical effect of stereotactic frame" and "brain surgery post-surgical facial swelling" and similar combination's and found nothing specific that spoke to any combination.

I do not have memory of my first 10 days post-surgery, none. So, I can speak to the recovery room as Peggy is able to do. I do know that my family was shocked, to say the least, at my appearance.

I do not understand why more NeuroTalk - Parkinson's Disease forum members are not joining this discussion and the discussion in the Clinical Trial forum.

I am quite puzzled about this.

I have a couple of thoughts to add here...first, I don’t know what role the FDA plays in the use of sham surgery in these trials (require? suggest?) but I think it's important to tease some of these basic issues apart regardless--some issues are about sham surgery as a tool for determining efficacy and some issues are around the ethics of sham surgery.

Starting with the value as a tool for interpretation....In phase I trials, where the goal is simply (and importantly) to ascertain human safety of a treatment you would not see a placebo group and therefore sham surgery is irrelevant. In the Ceregene phase I for instance, there was no placebo group.

In phase II trials, where the goal is continued safety monitoring as well as hints of efficacy, you might expect to see the double blind, placebo controlled trial design. Given the strong positive responses we often see for many phase I trials in PD there is great weight given to structuring trials in ways where one can observe true treatment effect. So the important question is how do you accomplish the “blind” in a delivery strategy such as gene therapy. Although there is probably no perfect way to completely guarantee a blind to the study, most stakeholders (sponsor, trial sites, IRB’s and patients through informed consent) settle on the sham surgery as the best way to test this type of treatment. Also, the trial sponsor itself (typically a company) needs to get the most informative read-out possible as it contemplates taking the treatment to the next experimental phase. If there wasn’t a sham option at phase II and potentially robust placebo responses persisted, the company might naturally (and ill-advisedly) continue on to phase III… At phase III, more patients are exposed to the treatment (again, in this case, a high-risk surgery is involved) and the costs are significant as the study population is expanded.

Jean’s question seems to merge two questions…if the treated patients react so obviously different to the untreated participants then one would expect that the blind would be useless and we’d see no placebo effect. In the case of Ceregene, if in fact the treated and untreated had any different responses, it didn’t negate the placebo since a statistically significant improvement was measured in both groups...ie, no hat was tipped.

The ethics of sham surgery can be viewed many ways I’m sure and is likely (as almost anything in the ethics field) a matter of personal interpretation. For instance, where a high-risk surgery is undertaken, neurologists commonly state that they won't consider prescribing such a treatment without evidence from a controlled clinical trial that it is efficacious (which includes beating placebo). In their mind it is unethical to subject a large patient population to such a risky procedure without evidence that it works and the benefits of treatment outweigh the risks and are measurably better the existing, alternative treatment options. I guess in a sense, they weigh the consideration of a few who, with informed consent participate in these trials (and are possibly subjected to sham surgery) versus the consideration of later inappropriately making the treatment available to much larger numbers.

Not sure I’m clarifying much but trying to bring additional perspectives to the discussion.

Debi Brooks

First- thank you, Debi for responding.

To my understanding - the FDA allows sham surgery but it doesn't have an official policy where it recommends the procedure for trials.

Since DBS surgery went through trials without using sham surgery, i still don't understand why current gene therapy trials insist upon sham surgery.

Even though I am an outspoken advocate in support of clinical trials, and I have already participated in 4 trials, I will not join a trial where sham surgery is part of the protocol.

Thank you, for your candid and interesting remarks, Debi. But just this morning I was talking to a participant in Phase II Spheramine trials, which as you know did not meet its endpoints (i.e. the predicted efficacy), and I want to add some thought to ponder.

The Pipeline Project, which is a grassroots group who support a speedier approval process of drug and treatment approval, have been looking at the pros and cons of sham surgery. I have heard both sides of the theory - some doctors say it is absolutely essential; others just say "it's required for approval." I am sure our fearless leader, Perry Cohen, will have some remarks to add here.

Back to my reason for talking to the Phase II participant this morning. We have had three major trials that showed great promise in Phase I trials, and up to the time of examining results statistically, were all three showing "observable improvement" in participants in Phase II, that were surprising, even shocking in some instances, when Phase II results did not meet endpoints. I am speaking of these trials: GDNF Spheramine - and the recent gene therapy - CERE-120 - all using surgical intervention - all using sham surgery (phase II) - and all open label in phase I (the participants knew they were getting the real thing). I wa wanting to hear from those who experienced first-hand the actual good and bad of the use of sham surgery in these trials.

The Pipeliners are preparing either another article or a new presentation (or both) on the ethics used in PD surgical trials. (I invite you to read our article in full published in ASENT (Journal of the American Society Experimental Neuro Therapeutics) at our website: www.pdpipeline.org )

Abstract: Ethical Issues in Clinical Neuroscience Research:
A Patient’s Perspective

Summary
A patient-centered paradigm for clinical research and medical care is presented as a solution to the problem of declining innovation and increasing costs and development time in the pipeline for new therapies. Fundamental differences in values and motivations among scientists, clinicians, industry sponsor, and patients in neurotherapeutics provide a framework for analysis of ethical conflicts and the loss of public confidence in medical research. Parkinson advocates’ views on clinical trial participation, perceived risks and benefits, placebo controls, and sham surgery are presented. These views reflect the sense of urgency and the unique perspective that comes from living with this progressive, debilitating condition full time. A patient-centered paradigm that includes authentic voices of patients as collaborators at every stage of development will help to resolve conflicts, build trust, recruit trial participants, and accelerate new therapies. Key elements are adaptive clinical trial methods and the development of information technology for the assessment of outcomes and surveillance of safety over the life cycle of a medical product. Supported by the Parkinson’s Disease Foundation, the Parkinson Pipeline Project is a grassroots group of Parkinson’s patients whose goal is to represent an authentic voice for patients in the treatment development process. This group promotes education and communication between members of the Parkinson’s community and active stakeholders in medical research, industry, and regulatory agencies. Its members are an example of a new breed of knowledgeable consumers, armed with first-hand access to research findings and reinforced by on-line connections to like-minded peers throughout the world.

Let me continue - when talking with this person this morning and bringing my thoughts together of conversations with at least two more participants who were in the gene therapy trials (one got the real thing and one got "shammed,") I don't believe anybody thought about the emotional aspects that were involved in being a participant in such trials. For some, to find out that they had sham surgery when they thought and analyses indicated improvement in symptoms - well, it was devastating to that participant.

I will not go on here for now (but would love to discuss this further) as I sam sure others will have plenty to contribute. But I do want to make a plea for anyone reading this who participated in a Phase II trial fo either GDNF, Spheramine, or CERE-120 to contact me via Private Message and I would like to talkk with you offline or via private email. In my opinion there's enough to warrant further investigation into the ethics of using sham surgery for Parkinson's.
Peggy

Again, I'm no expert but it may certainly be the case that the portfolio of considerations for each trial will differ, and hence lead to different design elements. But, it would seem that the role of the sham surgery in helping determine efficacy (or lack thereof) in the Ceregene trial was vital.

Peggy raises a different question...one of how well does any patient understand all the implications of participating in trials. Informed consent is a challenging and ongoing area with focus for improvement, no doubt.

Re the trial design differences for DBS ... I don't know but would offer that DBS is a symptomatic treatment where the surgery implants a device in the brain but the "treatment" comes from turning on the device not located in the brain...maybe that changes the confidence/nuance about ability to blind--the flind would come from turning on/off but the implant would have to take place regardless?

Just guesses.

Peg, Thank you for the invitation to jump in here, As you know when we published the paper in "neurotherapeutics" last year, we were concerned about how the so called "gold" standard has blinded researchers from using their brain to comprehend what the data are really saying. Large, unmistakable placebo effects are generated in surgery studies. Our concern then was about the dismissal of the placebo effect as bias was contrary to the history of medicine, and denies the human element, where hopes and expectations play an important role in healing, would undermine the treatment. Then after 2 additional failures of sham controlled studies, where we know from 1st hand experience that the therapies have lasting effects for some people , we began to look more specifically at the research literature on placebo effects, DBS, and sham surgery (I want to give special acknowledgment to Stan Planton, from Ohio for his amazing research skills to sift through the abundant noise to zero in on relevant published data). This was not just a difference of opinion about patients taking risks, but it may be affecting the results of trials, by creating bias in unintended ways Our arguments are summarized in a comment on the Alzheimers Research Forum. I will add more comments later.

Perry

I should add one comment...in these threads the topic of sham surgery (utility? ethics?) have been intertwined with discussions on placebo. MJFF has been interested in placebo effect for some time but we've struggled with zeroing in on what meaningful ways, if any, we can add value/take action. This conversation has been continuing in the wake of the failed Ceregene trial and was discussed at our recent Scientific Advisory Board meeting as well. While we haven't sort out a concrete path forward for MJFF-driven efforts, I want to share that we are working on it.

Debi

For people who did well in the Ceregene trial, I wonder if the placebo effect were part of doing so well?

As others have stated earlier in this thread, placebo effect is very much present in our clinical trials.

Good morning!
Thank you for a lot of thoughtful discussions this morning and I am trying classify them in my head. So please bear with me. It looks like (as some of you already pointed out), there are several issues to sham treatment, such as

1. Ethical issues related to Surgery
2. Ethical issues related to how informed are patients about "informed consent".
3. Emotional factors involved
4. Scientific rationale for doing sham surgery
5. FDA rules and regulations
6. Financial reasons

Obviously they are all tied together. But if we can come up with pros and cons for these points, we may come to some sort of an answer fo doing sham procedures. Thats my two cents worth on this topic!

Girija