Sham surgery for controls in clinical tri... - Cure Parkinson's
Can people share comments on their vote?
I voted "worthwhile in most cases" because we often can't avoid creating an ad-hoc control group to measure the benefits of the treatment. If we had reliable biomarkers, based from a significant population of patients and if we could extract a sub-sample close enough to the tested cohorts, then we won't need sham surgery.
So we should definitely try to avoid sham surgery that brings a lot of issues on the moral ground, but what could be the subtistute when all the ifs are not satsified? Novel ideas most welcome.
The question has no meaning unless a context is given. For example in wich conditions is the sham surgery performed? It could be defensible if it just delays the real surgery within a period not harmfull as clinical consequences are concerned.
I'm afraid that I think it is 'barbaric and unjustifiable. But this is just an opinion, not something I would want to foist on anyone else. I would rather see a debate on it. My reasons for it are that people who are struggling with PD are put, for an undefined period of time, sometimes extended, under the stress of not knowing whether or not they have received a treatment. And they are given a surgery that leads them to believe that they could have had the real thing. It is the mental to-ing and fro-ing that I think it a problem, the do I , don't I aspect. I may be naive to think this, but I have read quite a bit about sham surgery, and sat through the very informative footage of a 2 day conference of top doctors, and I still think this. Technology, especially imaging, is developing very fast, and I hope that someday this practice will come to be seen as I see it, by medicine and science. I also have reservations about it because of the whole dilemma of PD - that nobody seems to be sure that we are seeing one specific condition, or whether it is actually a spectrum of disorders.
Here is an article just published in Nature magazine which deals with this subject from all perspectives. It draws the conclusion that sham surgery could in fact be 'killing off valuable therapies for Parkinson's'
nature.com/news/2011/110810...
While writing I have pasted in below my own thoughts on this as presented at a recent conference in Sweden - Tom
Sham Surgery in humans is inhuman
In medieval times, when people were accused of some wrongdoing, the only way to preserve their integrity was by taking part in some ordeal. These so called “trials” were often so heinous in nature that people died as a direct result. Death, during or after the trial was viewed as a good thing. It meant the person accused was actually innocent. If that person survived, this was considered as proof that he/she was guilty. As a consequence, this person was hung, drawn and quartered and decapitated anyway. Fortunately, contemporary judicial trials are not controlled in such a randomized way and rely on factual evidence and precedent rather than blind faith. This is not the case in medicine, however, which has clung on to the concept of randomised, blinded studies as a means of establishing integrity. But is this integrity flawed?
To those of us patients upon whom these methods are employed there is perhaps an understandable view that the current system of clinical trials draws certain parallels with the medieval “trials by ordeal”. If the therapy does not work, then its development is stopped immediately. And if it does work, then the presumption seems to be that improvement must be related to a placebo effect. This then results in further more detailed trials on ever-increasing numbers of people until either time and money run out or someone can come up with a decent reason to stop the therapy reaching the clinic. Either way, just like the accused in medieval times, we patients are doomed anyway.
But this of course is just a perception. Or is it? My job today is to persuade you as scientists engaged in the noble pursuit of scientific integrity and evidence-based medicine, that sham surgery is not justifiable in humans. And I am also going to suggest the reasons why we, here, in the Parkinson’s community, need to look to a more innovative and inclusive means of outcome measurement which better reflects the changing culture of medicine and also better reflects the reality of living with a chronic neurological illness in the 21st century.
So let’s start with this very point - “the reflection of reality”- because this goes right to the heart of why the practice of sham surgery in Parkinson’s is not only inappropriate, perhaps even disgraceful, but from my perspective as a humble non-scientist, it also seems to be a practice totally lacking in logic.
As in a judicial trial, the results of a clinical trial depend wholly on the evidence submitted. For this evidence to be accepted, it must be verified as authentic. In other words it cannot be tampered with, nor can it be artificial, incomplete or subjective. It must be factual, relevant and based on reality. Sham surgery is quite clearly none of these.
Firstly, the placebo effect is a real effect and to discount its impact when assessing a particular therapy is to introduce a major artificial component in the overall analysis. Also, if you discount the placebo effect in trying to measure the net effect of a particular treatment, you need also to take into account the opposite effect which is likely to be more marked in trials involving surgery due both to the idea and the reality of the invasive nature and the likely pain involved. This is often referred to as the nocebo effect.
Similarly, there may be a further psychological effect at work, namely that there may be some research participants who interpret their response to the real treatment as placebo, and therefore will experience a downgraded beneficial effect due to a lowering of expectations. Finally, in sham surgery the placebo effect can relate to three very different types of effect. It seems to me it is impossible to distinguish between the following:
• Firstly the true placebo effect i.e. a sense of better well-being without physiological effects;
• Secondly, there is what Moerman and Jonas described as the “meaning response” in the brain which does cause physiological changes and potentially would not be a factor if there was both optimal and equal care throughout the Parkinson’s world.
• Thirdly, there could easily be an actual response to the nature of the sham surgery in the same way as there arguably is an actual response from an acupuncture needle.
All these points render the placebo effect in neurosurgery extremely difficult to assess and I do not see any rationale that sham surgery can be reasonably supported as a means of introducing greater accuracy into clinical trials or as a way of assessing the reality of living with Parkinson’s.
But these are not the only flaws with sham surgery. There is of course the obvious issue of safety. I would remind all those here in favour of invasive sham surgery of the first law of medicine – “Primum non nocere” – (first do no harm). No wonder they call this the hypocritical oath instead of Hippocratic oath.
But in all seriousness, Macklin, in the New England Journal of Medicine in 1999, suggested that “performing a surgical procedure that has no expected benefit other than the placebo effect, violates the ethical and regulatory principle that the risk of harm to subjects must be minimised in the conduct of research”.
But none of these issues actually represent the fundamental and profound reasons why I am so against sham surgery. And so, here we get to the crux of my debate, and I have three points, all of which, I think, suggest that sham surgery has no place in Parkinson’s.
Firstly, the current system of clinical trials has not adapted to a paradigm shift in medical culture. It has not embraced the fact that Parkinson’s patients are living with their condition for 40 or 50 years and are looking for more urgency. It has not embraced a more patient- centric model of analysis when considering new therapies. It has not embraced the information and technology revolution which has resulted in proactive rather than passive patients. It has also not embraced the call for transparency of data to better inform and equip the clinical trial process and ensure it is conducted using state of the art science and the most up-to-date techniques. In short, the procedural side of clinical trials needs a radical overhaul if it is to keep pace with the quickly evolving clinical arena where patients, like it or not, are becoming increasingly influential. How long, realistically, can something like sham surgery endure in such an environment? I urge you all to consider this now and come up with novel solutions and to keep pace with the changing landscape of medicine. My own organisation, The Cure Parkinson’s Trust has just won a European grant looking at this very issue.
It is no good any longer to expect patients to enter trials and remain blissfully unaware of what they are taking and the context in which they are taking it. The people with Parkinson’s I know would all expect to be informed every step of the way. They would expect not just to be involved in the provision of the physical data from the study; they would expect also to contribute substantially to the intellectual data. And here I am talking about having some say in the protocol; in the risk and benefit equation; in regulatory and ethical aspects and, of course, of having greater importance ascribed to patient reported outcome measures.
With these points in mind, I would argue strongly that the fundamental fabric of a clinical trial needs to be measured against a background of reality – not one of manufactured ignorance. Furthermore, if you engage your trial participants in the wider relevance, application and importance of the study, this will more than likely have a positive impact on the accuracy of the results. By engaging Parkinson’s patients in all aspects, not only will compliance improve, but there is a far greater likelihood to secure more objective, more informed and more accurate patient reported outcomes. To attempt to induce a lack of expectation in Parkinson’s trial participants is ridiculous – we are not daft – there would be no need for a trial at all unless there was an expectation of some therapeutic value by someone.
Finally, there is the issue of personalised medicine which is so relevant in Parkinson’s management and is now seen as a crucial component in the optimisation of day-to-day quality of life. This approach needs to be adapted and employed in the clinical trial arena, otherwise it will not correspond to reality.
My second point is that it defies me how anyone can justify the use of sham surgery as a method of assessing a condition where the basic framework of outcome measures is so fundamentally flawed. Current measurement scales in Parkinson’s offer only a snapshot view of the condition. They are subjective. They rely heavily on the vastly differing skills of the assessors. They take little account of the individual nature of the people involved, or the individual nature of their condition. Surely, surely, surely, we need to get the overall assessment of Parkinson’s so that it truly and adequately represents a person’s quality of life. This has to be addressed first. Generically applying a value to someone’s motor symptoms at a single point in the day is not good enough. We must devise a patient-centric means of assessment which reflects reality. Until this time, there is simply no justification for sham surgery whatsoever.
And finally, my third point is that it is my solemn hope that most of the surgical trials for Parkinson’s will be for treatments which are disease-modifying in nature. These treatments need time to work their magic – typically between 6 and 18 months before the true extent of their benefit is established. This length of time dilutes the tangible impact of a placebo effect, the benefits of which I would hope would be no match for the improvements we expect to see in the type of therapies which are currently in the pipeline. This for me is the cast iron proof needed to demonstrate that there is simply no need to even contemplate sham surgery for Parkinson’s.
So, when someone asks me whether sham surgery is a necessary evil, there is a phrase we laymen use which is incredibly appropriate as a response: It’s a no brainer. There is no justification for any type of sham surgery in Parkinson’s and I therefore commend to this audience of illustrious scientists that this practice is terminated before a patient is.
Brief discussion after the talk
The acceptability of sham surgery in the context of translational stem cell research. On the one hand, it can be argued that sham surgery is not viable from the patient perspective, since research projects will not be able to enroll enough persons if they know that can be subject to sham surgery. On the other hand, some argue that hope is desperate, and there will always be patients who will enroll with the hope not to be allotted into the sham surgery arm. There is a perception that patients are desperate and this is the reason why they will join any trial – even if there is sham surgery. However, desperation does not imply that decisions are made without considered thought and without having regard for the risk/benefit ratio. Hope is often blind through an ignorance of facts, but is rarely a precursor to making choices out of desperation. Hope is only perceived as desperation when patients put too much faith in their medical advisors on what is best for them.
From the perspective of researchers, they have to convince the health authorities that the stem cell-based therapy works. Health authorities may require that the efficacy of these therapies has been shown in sham surgery-controlled trials. Researchers need to tackle this view. However, if they leave the idea of sham surgery, they need to replace it with something that is well-defined, for example, a follow-up of 20 years. It is unlikely that patients can still experience a placebo effect after 20 years. The follow-up would be very necessary for the patients. The problem is, however, that a study can hardly be designed as a study of 20 years. However, the technology has advanced and there should be a better way to objectively measure the improvement in patients instead of comparing them to a control group who has received sham surgery.
The article nails down most of the issues and in particular "Researchers use placebo controls to weed out false positives. But for patients, the real ogre is the false negatives"
Eventhough I believe it should have been stated that false positives are also an ogre for the entire community of patients (imagine that we found today that after all, L-Dopa has no real impact)
But I would go back to @JaturSerrano's comment, we would need to set a context to define if we really agree to disagree, or if we're not answering different polls. My understanding was the same than @JaturSerrano's: "It could be defensible if it just delays the real surgery within a period not harmfull as clinical consequences are concerned."
Actually, I would be much less scared by false negatives if potentially interesting IP material, like patents on GDNF, were easily accessible to startups through patents pools.
There, my comment on a recent FasterCures' post for more context fastercures.blogspot.com/20...
"Current measurement scales in Parkinson’s offer only a snapshot view of the condition.
They are subjective.
They rely heavily on the vastly differing skills of the assessors.
They take little account of the individual nature of the people involved, or the individual nature of their condition.
Surely, surely, surely, we need to get the overall assessment of Parkinson’s so that it truly and adequately represents a person’s quality of life.
This has to be addressed first. Generically applying a value to someone’s motor symptoms at a single point in the day is not good enough."
I have separated each point out in this paragraph of Toms article. Until these things are really sorted out ALL trials, not just sham surgery, are a lot less objective than they may seem to be. Patients know this. Patient volunteered information is considered to be extremely subjective. Maybe this is less so than is believed, as we have to objectively deal with the daily reality of living with PD and managing medication so we can function. This is where patients, doctors and researchers could come together to develop new solutions on how to assess PD.
I am really pleased at the extent to which this has been discussed already. I feel this should be given a fuller discussion on the parent site (parkinsonsmovement.com). we will set up a proper debate in early September.
Tom - thanks for posting this article. Perry Cohen is responsible for getting me involved. It will be the success oof all PD grassroots' efforts to stop sham sur ge ry. Where is the practical thinking with these people? We don't even have a good way to confirm PD and we're drilling in peio;e's heads! The anesthesia risk itself is one to ponder. Oh, don't get me started.
A simplistic way to view this is by asking some questions anyone can apply:
1) Would we dare to take someone to do hip surgery with out a confirming x-ray? (Remember, there is no test to comfirm PD)
2) Did we do sham heart transplants?
(If we did, I missed it!)
3) The "placebo effect is so strong with PD" is often an excuse given in support of sham protocol, but in my opinion that gives even more credence to reasons to NOT do sham surgery.
4) Why in the world are we "faking" surgery on the most vital human organ in our body? Yes, if we didn't have a brain, we wouldn't be able to make our heart tick. Nothing works independent of our brains . . .
JUST THINK ABOUT IT!
