I erased that part because I thought it sounded redundant and I felt like a nerd...I can't explain it....just paranoia.

And you replied with detail to them all...I really appreciate that post. I couldn't help but be drawn to the statement about trials possibly be designed more overtly. Hoping for updates..they end speculation...second guessing can drive you a little dingy...lol

i think we all needed that,
paula

There is NO such thing as a sham surgery for DBS trials anyway IMHO. First you are awake for it, and all the preparation for it, mounting and aligning the micro drive would be the first of many ways you could tell, others include the Micro Electrode recording, the actual placing of the lead, testing of same, the "honeymoon effect", to the one or two lumps that are caused by the IPG's which incidently you can test with an AM radio.
I think the actual process would give it away whether you were implanting leads or GDNF or what ever.
You could go from the trial drug to a placebo, or vice-versa, if there was some sort of metered delievery system. I think however that would be confusing to the tester and the the recipient.
Interesting thread!!

Charlie

Thank you everyone for your thoughtful responses to this critical subject. As I said earlier this is THE most important issue for today's PWP, and even more for those of us past 10 years, who cant weather another failure. Thank you especially Debi, for your characteristically crisp and thorough illumination of the key points. I am certain that you will find very insightful PWP with our unique 1st hand experience as participants in studies as eager collaborators to sort out these issues.

My view is that the DBS example offers what should be an acceptable alternative to placebo brain surgery, which is at best marginal ethically due to the risk to volunteers assigned to placebo with no expectation of benefit (what medical ethicists call therapeutic misconception). Participants in clinical trials for surgical interventions will inevitably have high expectations for the treatment. Why else would they take the risks of experimental brain surgery?

Placebo Response in reality vs experiment

As stated, in my previous comment, the research literature on placebo response not only shows extraordinary impact on PD symptoms, but also shows that it works by release of dopamine through the same brain pathways that are used to control movement.. Pain research indicates the need to potentiate neurological pathways for the full effect of the treatment. Particularly problematic for the placebo surgery is the bias introduced by randomization in the context of an experiment, that can in fact dilute the placebo response in the treatment group leading to type 2 errors (false negatives). As detailed in my previous comment, the data from three failed phase 2 studies are consistent with this dilution of the treatment effect when compared to Phase 1 open label (no control) studies that are more like real life.

Bias

Biases to results can be introduced by the extraordinary power of sham brain surgery as a placebo in the context of an experimental protocol with randomization to treatment and control. Blinding patients to sham brain surgery undermines the effect of the therapy by lowering the expectation for improvement in the treatment group due to the % chance that they have the "real thing' and conversely raising expectations in the control group The DBS study avoids this most often overlooked bias by randomization to treatment and best medical treatment.

Clinical trials in depression, which also fail at high rates, offer guidance for minimizing noise in measurement of subjective end points such as UPDRS., including centralized rating and averaging several scores. In the absence of more precise biomarkers as surrogate measures for end points, all avenues to minimize measurement error need to be employed

Efficacy

We still have to address the question whether the treatment does anything beyond the placebo effect, and for Cere 120 the case is still out, but we know that placebo effects do not last indefinitely. If they do I would settle for a placebo cures. (I agree with Jaye that a person’s attitude, hope and spirit are crucial to the cure, but this is not a new concept in medicine). I am aware of a number of other study designs that can provide evidence for long term efficacy, such as cross-over or delayed start designs, that can be employed while long term safety data are accumulated.

Other Issues

One issue that has not been raised relates to gene therapies and cell therapies that are one shot treatments, which of course have big advantages if they work. They have a big disadvantage that they cannot be readily fine tuned or turned off, which would be necessary for some designs. Companies would have to do extensive dosing studies, which is often to convince PWP that they know what the most effective dose is.

New FDA law provides more flexibility to grant conditional approval while the long term safety and efficacy are established as more patients are exposed to the treatment the treatment. Medicare and other payers provide reimbursement for treatments in such protocols. Earlier revenue would mean a lot to the financial health of the startup companies where most innovation comes from.

BIOMARKERS

The availability of validated biomarker for HIV has reduced their drug pipelines to 3-5 years. My conversations with the leading FDA regulators dating back 8 years now, have emphasized the importance of these tools, whose value is well recognized. Dr. Katz has a well thought out argument about reasons for insisting on higher standards of evidence for validation of biomarkers than required by law (which requires reasonable evidence that the marker correlates with reversal of disease processes as well as disease progression and decline of funcgtion) but he wants demonstrated measures of these markers.

I am aware of the emphasis that MJFF has placed on the research into biomarkers, so I would like to encourage them to join the Coalition Against Major Diseases, which is a collaboration among 15 large pharmaceutical companies and patient advocacy organizations for both PD and AD in close cooperation with FDA staff. Their aim is to create the information infra structure necessary to facilitate development of ‘pre-competitive tools for use by all to accelerate product development. The initial work plan is to validate and qualify by FDA both bio markers and disease progression models.

I have been trying to encourage the staff of the coalition to expand their agenda to include patients and doctors for self care and medical management of care in the form of Electronic Medical Records and Personal Health Records. .Now with recognition of these information tools as the center piece of health reform maybe their interest will grow ($19B for EMR in the Stimulus law just passed. But this is another story.....

Perry

Sham surgery should be outlawed, people can and do die from
any surgery, and this will be done to a patient who is already ill...
I believe this is still very barbaric - rates right up there with blood letting~!
Shame on sham surgery!!
if the drug or sugery will work - it will depend upon the efficacy of the
drug/ or the danger of the surgery
we are human/ not lab rats!
sorry - this is still inhumane in my opinion!
sincerely,
tena

hi perry,

sorry for being a little late to the game.

i am intrigued by your questioning why the placebo effect isn't just considered an integral part of an effective therapy... my question is, if it were, would that eliminate the need to determine whether there is any non-placebo therapeutic benefit from any given therapy?

wouldn't we want to know if benefit were entirely attributable to placebo effect? if we would, there would still be a need for placebo-controlled trials, wouldn't there? if we wouldn't, then would we be effectively deeming the placebo effect an actual therapeutic benefit? we would have to be, i would think... which would then lead to trials testing different methods of producing placebo effect against one another... just thinking out loud here - this was not my original question.

my original question relates to the following statement:

"That is so because random assignment dilutes positive effect of patients’ expectation that they will improve from the on-going uncertainty about whether they are on the real thing, and conversely it elevates the placebo group’s expectation that they may be on the real thing."

if there are both positive and negative placebo effects, then, assuming blinding is effective, the former could not affect just the placebo group and the latter just the group receiving the real thing - the potential would exist for each participant, regardless of which group, to be experiencing positive, or negative, or both effects.

thus, if blinding is effective, wouldn't one have to assume that each of these potential effects would occur, on average, with the same frequency and to the same degree in both the placebo and the real thing groups?

thanks for your help
rosie