When there is invasive brain surgery - as in the Ceregene trial for the participants who got the real treatment, would those participants have a different, more severe case of facial swelling than the participants who had "sham - the burr hole" surgery? And would the participants who got the real treatment (i.e. invasive surgery) have other different, and more severe reactions after the surgery?

I don't have any facts one way or the other, but I think this is a question that researchers should honestly answer.

Because if my supposition is correct - that physical reaction after sham brain surgery is different from invasive brain surgery, then having sham brain surgery doesnt produce a truly "blind" trial. And that would be a BIG reason to rethink and hopefully stop this sham surgery business.

Jean - your question came up in our other forum on clinical trials - "CERE-120 The Story". I have copied my response below:

I had brain surgery and was not told to "expect" swelling (and I was in an open label study; i.e. I knew I was getting the real thing.) To say this would probably unblind the placebo group almost immediately. And for the most part I didn't have much swelling; I imagine the amount of swelling would be determined by how much trauma was inflicted to the brain.

There was a puffy kind of look on my eyelids (which several have said is indicative of brain surgery). It was like my eyelids became thin and fleshy and seemed to pile up on my lashes. Of course the doctors and nurses caring for these patients would recognize the post-op appearance of one who has had brain surgery, but they have been trained accordingly. Only the neurosurgeon would know.

I also know that each patient's response to any type of surgery varies greatly. For example, after my surgery (Spheramine) there was an overnight stay in ICU (Intensive Care Unit) built into the protocol. I recall awakening in the recovery room awaitingn my transfer to ICU. However, I had this euphoric feeling (an almost "I'm cured!" feeling that lasted for about 2 weeks). I was very talkative and remember telling the male nurse in recovery every clean or semi-clean joke I knew. About a half hour later, I saw him on the telephone with his back to me, obviously trying to hide his conversation from me. He was talking with the neurosurgeon (I found out after he hung up). And this is what he said, "I CAN'T sewnd her to ICU! She's sitting up telling jokes!" So I went straight to the regular room, where I stayed for 3 days.

I recall wondering why my movement disorder specialist didn't visit me (the research nurse did, but it was on the day of discharge when swelling was minimal). In retrospect it must have been because he would have recognized the swelling or "fleshy" eyelids and the study would have been unblinded.

But Jean, this means the bedside caregivers, and in this case POSSIBLY the research nurse, would recognize the after effect of actual penetration of the brain's dura (in sham surgery, they drill the hole, but don't penetrate the dura). That is putting a lot of trust into those people, some even non-professionals. So there is a big chance someone might leak those receiving the real therapy, even unknowingly. Therefore, this is even more reason to add to taking a long look at the validity of using sham surgery.

Peggy

If the after-effect of actual penetration of the brain's dura (in sham surgery, they drill the hole, but don't penetrate the dura) is different from the after-effect of true invasive brain surgery, then how can researchers claim the study is blind?

This question must be pursued because in my opinion, if it turns out to be true, then it is a big strike against using sham surgery.

Good morning!

All the talk about placebos, appropriate controls and FDA rules, made me look back into my folders about a gene therapy clinical trial I was familiar with. It was gene therapy for haemophilia by providing factor VIII using a gutted-adenoviral vector. It was in 2002 and was one of the first few gene therapy trials with adenoviral vectors. This FDA and RAC approved clinaical trial protocol had no placebo controls to compare with. It was assyaing for factor VIII before and after treatment . It was a Phase 1, and the end point was detectable factor VIII and of course the safety issue that is associated with using adenoviral vector. My involvement in this trial was minimal, and do not have many required details and thats why I hesitated to post it here. But it might be useful info to know that FDA did approve a gene therapy protocol without an appropriate, untreated/vector alone group. It all depended on how the protocol was written and justified to the FDA.
Thanks
Girija

Someone needs to correct me big time if this isn't correct, but I don't think it's written anywhere that a placebo is required for clinical trials. It's just a practice that the FDA requires...an unwritten "law"?

Girija, are you saying that there was a gene therapy trial with no placebo required?


thanks,
paula

Paula,
yes, thats what I am saying based on the information I have. Like I said , my role in that project was minimal and I do not have all the details. As I recall, there were only three patients for that study. It might have been a special consideration case. I will try to find out more from my collegues and post it .
Girija

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