There is an overwhelming consensus that double-blinded experiments, in which participants are randomly assigned to receive a placebo, result in the strongest and most reliable evidence – which means they give us the best indicator of which experimental treatments would truly help people living with PD and, just as importantly, help shield people from treatments that don’t.
This scenario gets more complicated when the new “drug” is actually a surgical intervention, in the case of PD, brain surgery. What is the surgical equivalent of a sugar pill? It’s called sham surgery and it’s not simple.
So the National Institutes of Health (NIH) held a two day conference, part of which is now available to view online via videocast, to discuss the scientific and ethical considerations underlying sham surgery for neurodegenerative diseases, chiefly Parkinson’s disease.
Why Sham Surgery?
Essentially, a clinical trial is an experiment where the results are unknown. Sure, previous data or testing indicates it is worth spending loads of money on it; but, really, no one knows how the experiment or trial will end...at least that is how it is supposed to work. But because clinical trials are experiments involving humans, the process can quickly be biased by what people think or are expecting to happen: people with Parkinson’s believe they may be getting better and their physicians may too easily agree. Enter the very powerful and very real placebo effect in PD (see here and here for two studies highlighted by panelist Jon Stoessl, M.D.).
So if you have PD and the placebo effect can help you feel better, what is the big deal? Why not spend all this energy making the placebo effect better? The problem is the placebo effect works by convincing the individual something is real when it is in fact not. Before science entered medicine, placebo was mostly the only game in town. So while studying the mechanism underlying the placebo effect is a worthy vein of research, the placebo effect remains no substitute for medical therapy.
A solution has been to control for the placebo effect by keeping everyone in the dark (also called blinding or masking) about who is getting the experimental treatment and who is not. This way, designers of clinical trials try to eliminate the obvious forms of bias, like the placebo effect, as well as not so obvious forms of bias that are harder to predict.
Many PD therapeutics, however, start out as open-label trials where no secrets are kept and everyone knows who is getting the experimental treatment. It may not be surprising, as noted by meeting panelist Steven Piantadosi M.D., Ph.D., that these early trials often end in success —frequently demonstrating a 30 percent improvement in PD symptoms — yet are later thrown upon the bin heap of failure once the more rigorous experiment is conducted. With so many successes followed by failures, what is the price to the person with Parkinson’s?
There is no easy answer to this multi-faceted problem. However, several ideas emerged from the discussion at last month’s meeting.
- Be more rigorous in the preclinical stage. Without a true model of PD in animals, investigators need to be more thorough in understanding the biology behind a treatment before trying it in humans. (Mice are not people.)
- Early trials should be large enough to detect potential adverse events and should include some form of blinding to make them most informative about future directions.
- Sham controls should minimize the risk to the participant by using minimally invasive procedures.
- If the results of an open-label study are used to decide whether to go forward with more testing the treatment effect should be very large.
These are just a few of the suggestions that emerged to minimize the use of sham surgery while maximizing its scientific potential when employed. As the draft recommendations are refined by the panel participants, they will be available for public comment. We will let you know when that happens, so be certain to check back.
What Do You Think?
So what are your thoughts on how clinical trials are designed and conducted? When would it be appropriate to use sham surgery?