Jean
 

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 awaiting 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 (he was a cutie!). About a half hour later, I saw him on the telephone with his back to me, obviously trying to hide his conversation. He was talking with the neurosurgeon (I found out after he hung up). And this is what he said, "I CAN'T send 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 my discharge day when swelling was very 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.

Peg

following up
 

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.

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.

delivery system of Cere
 

http://www.alzforum.org/new/detail.asp?id=2012#{68DBD971-5068-42CE-A192-DDE1CE32B3C8}

Within this news article is a discussion concerning Cere 120 trial results--cites researcher who feels delivery system at fault. Interesting/informative comments penned by Perry Cohen in comment section.

Perry's post to alzheimer forum
 

The question I want to raise regards the Ceregene 120 study, a gene therapy application of the nerve growth factor neurturin, NTN. The Phase 2 study "failed to meet primary endpoints" in comparison to a sham surgery placebo control. Similar to experiences with other surgically installed treatments, such as GDNF infusion pump and implantation of spheramine, a cell-based therapy using retinal dopaminergic cells, this latest placebo-controlled trial did not replicate the gains from the Phase 1 open-label study. The results of all of these studies are clouded from methodological issues such as differences in dosing between Phase 1 and Phase 2, dislodgement of pump connections, and differences in the use of other PD medications during the studies that may have affected the results. Even so, the fact remains that some study participants have experienced dramatic improvements lasting as long as six years and counting, and some have reduced their PD medications to near zero, being almost symptom-free after decades of increasing disability. A brain autopsy of one GDNF patient showed nerve growth in the side of the brain in which the treatment was administered during the trial. For all of these treatments, data point to improvements well beyond reasonable estimates of placebo effects.

Clearly placebo effects are very strong. Research on placebo response for a range of medical conditions including PD attributes these real physiological effects to expectations of benefit and conditioning established in the social context of administering a treatment. The greater the risk and notoriety of the intervention, and the more certain and authoritative the source, a greater placebo effect is produced. Maximum placebo effects, as would be expected, are found from brain surgery as well as from the safest form of sham brain surgery, where the brain is not penetrated but the patient goes through the same process including lengthy anesthesia. DBS patients report vast improvements in symptoms even before the stimulators are turned on. Clinical brain researchers (including more than 90 percent of the Parkinson's Study Group) agree that sham brain surgery is necessary to prove that improvements are attributable to the treatment beyond the placebo. On the other hand, an online survey of activist PD patients found that only 37 percent would participate in a sham surgery study. Closing this gap raises practical as well as ethical issues.

DBS was approved without sham surgery as a placebo control. So why aren't DBS's gains in motor scores attributed in part to a learned placebo response? Shouldn't the placebo effects that last multiple years be counted as part of the treatment, as they effectively are with DBS, and not written off as bias? The recent JAMA publication improved the evidence of efficacy for DBS by randomization to best medical treatment versus surgery. Why isn't random assignment to best medical practice a sufficient comparison for other surgical interventions?

Sham surgery is not a sugar pill; it is a powerful intervention, although you would probably be charged with fraud if you tried to sell it. Placebo studies on the experience of pain in fact demonstrate that the "bias" from patient hopes and expectations, a central element of all healing, is opposite of what has been assumed by science in experimental settings. That is, treatment effects are reduced and placebo effects are increased. That is so because random assignment dilutes positive effect of patients’ expectation that they will improve from the ongoing 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. This biases the results toward type II errors (false negative), which are more important to patients with serious illness than are type I errors (false positive) that are the target of statistical models. The pain studies suggest that the placebo mechanism may be necessary to trigger the therapeutic effects of treatment. Elaborate deception to control this effect could be undermining its evaluation.

Sure, we need to control bias. But variability and bias can come from many sources, including, importantly the selection of participants and the variability of raters on subjective scales such as UPDRS. For example, are all study participants diagnosed correctly? And do they represent homogeneous types of patients? Depression medication trials, which also fail at high rates, have taught us that clearer distinction between treatment and placebo results from higher-quality central rating of subjective measurement scales. Multiple ratings of key measures reduce noise in data when averaged. Patients who have participated in PD clinical trials know that UPDRS "off" may describe different behavior on different days, and are not totally determined by the time since the last dose. Better understanding of these factors from the patient perspective is necessary to control this source of variability in the data.
Alternatively, where the sources of variability are unbiased, the problem can be fixed by increasing sample size to account for random fluctuations in the calculations of confidence of the result. This not only costs more, but it also may bump up against practical limitations including recruitment and FDA statisticians.



Medical miracles of the twentieth century mostly pertain to acute conditions, where linear assumptions of statistical models for hypothesis testing more closely approximate the relatively short-term interventions. As we deal with longer-term degenerative processes involving dynamic interaction and feedback to our conscious brain processes, assumptions from the experimental model become questionable. This is true even where all orthodoxies of statistics are followed and statistical significance is achieved.

Recent FDA law offers greater flexibility to align methods to the parameters of the specific case. Such alternative methods need to be qualified and used. Examples include Bayesian statistics for application to dose-finding tasks, or mathematical models of disease progression as historical controls. Crossover designs can detect differences in symptomatic benefits, and delayed start designs have shown promise to detect neuroprotection.

FDA law requires well-controlled randomized studies, not placebos. New policies put more emphasis on life cycle monitoring of treatments in real practice settings, and provide reimbursement coverage for access to new treatments while evidence of long-term safety and efficacy are established with greater certainty. Following patients more closely for a number of years to see the lasting effects can establish whether the treatment effects are purely placebo, at the same time that long-term safety is tracked.

Rosetta Stones....very classy yeah!
 

the icon is the result of dyskinesia - i feel very positive about this post...lol ...I like being thought of as a rosetta stone! We all are, and the interaction among the rosetta stones - the healthy being just temporarily healthy as Sheryl J. says - can produce a new language. It's time to gather. There is a funny story about the word gather. I will write about it soon. It's one of those confirmations that you are on a good track [i would describe it as a spiritual energy - that's individual too!] And it's funny.


Is it Ok to copy a blog post? let me know as i know you must if it is breaking copyright. read it first...lol

For the life of me i couldn't get rid of that bold above....sorry. ok here's a cheer from Faster Cures.
Improving Clinical Trials: "Yes We Can"


by Kristin Schneeman, Program Director, FasterCures

Probably one of the most persistent problems slowing medical research that we hear about at FasterCures is that the cost in time and dollars of clinical trials is crushing the discovery enterprise. Professionals from all corners of the clinical research enterprise express frustration with the complex web of problems and the long-term gridlock they perceive. They are weary of devoting time and energy to any effort – whether a one-time conference, an ongoing process, a consortium or alliance – that will revisit the “same old issues” surrounding clinical trials.


In the spirit of the New Year, we’d like to highlight some heartening efforts from a variety of quarters to stop griping and try to solve some of these thorny problems. They’re all very different, yet what links them is their optimism that change is possible.

The National Cancer Institute and the CEO Roundtable on Cancer are engaged in an ongoing effort to develop "model language" for use in the contract agreements that govern clinical trials. The model language covers seven areas in which negotiations regularly stall, including intellectual property, study data, indemnification, subject injury, confidentiality, publication rights, and biological samples.

Duke University is hosting an effort springing from FDA’s Critical Path effort, the Clinical Trials Transformation Initiative (CTTI). CTTI is a public-private partnership that will include broad representation from government, industry, patient advocacy groups, professional societies, and academia. Its more than 50 members will work together to develop new standards and identify new methods and technologies that improve safety, boost the quality of information derived from clinical trials, and make the research process more efficient. This is not another exercise in analysis paralysis; it is meant to be a practical effort to generate data and test solutions.

And finally, the Dr. Susan Love Research Foundation and the Avon Foundation have recently joined forces to launch the Army of Women Web site. This is a new and different way to engage people in clinical research – not a walk or a telethon, but an opportunity to directly contribute to research. Army of Women seeks to recruit one million healthy women of every age and ethnicity, including breast cancer survivors and women at high-risk for the disease, to partner with breast cancer researchers and directly participate in research; and to challenge the scientific community to expand its current focus to include breast cancer prevention research conducted on healthy women. Women can register to be notified of opportunities to participate in research projects (by mailing in blood, saliva, even breast milk samples, filling out questionnaires, etc.).

Within each patient is a Rosetta Stone of information that could unlock the potential to cure disease. It’s nice to know not everyone has stopped trying to solve the puzzle.

drugs are not the answer...
 

we have more drugs on this earth than people,
and perhaps the flushing of 750 million pound per year by US hospitals may be the reason we are ill,
I will not argue this point -
ER meds are there to help a person stop bleeding to death -
the drug problem is bleeding the ill people to death,
you can not live on pills alone...

simplify your life
turn off our brains and sleep... we can not enjoy life if we do not rest.
learn to live simply
eat well
love people, love children,
perhaps a love study may have miraculas results
and we can do that for free...