Hello,
Is placebo effect much more profound in clinical trials with neurological diseases or do you see it in many other clinical trials for eg: AIDS or cancer therapies? Do you have such data from your lit survey?

thanks
Girija

Girija,

I don't know - but Parkinson's always seems to be singled out.

Here is my personal story:

I was in the PRECEPT clinical trial for 2 years. During that time I was in an email group with about 15 other trial participants. A subset of the folks in my email group was doing very well - so well that they had no disease progression and didn't have to start "regular" pd meds. We all figured they were on the "good stuff."

As it turned out, these people were on the placebo, and as part of the larger placebo group, their group did better than the people who were taking the experimental drug.

I was in the group taking the lowest dose of the experimental drug, and my group did the worst (go figure!)

Again, not an expert but I've heard this discussed frequently in scientific meetings and two bits that come up regularly that might be of interest...

placebo is a biological effect and is found in all sorts of diseases/interventions...it does seem to be particularly vexing in PD...why? the placebo is believed to occur in some part due to triggers in the reward system in the brain--guess which chemical? dopamine. So, in a clinical intervention that actually targets the dopamine system directly or even peripherally, such as many treatment strategies in PD, you have the extra confounding effect. I think there is data that suggests placebo effect can linger particularly long in PD too (many years after intervention).

Debi

My interest in this topic, and I think I also can speak for other activist PWP, is motivated by my 13 years with PD. . Time is not neutral for a person with a degenerative disease, so a failure of a clinical trial that not only drains resources to redo the study correctly, but sets back the whole program years if it is not discontinued altogether.

Our goal in the Pipeline Project is to alert the sponsors and the regulators about potential errors that they can, and from our growing experience in advising sponsors and regulators, they often do make in their assumptions and design choices. Shedding more light on the previously totally proprietary interactions betwen sponsors and FDA, where the critical choices are made, will improve communication about the options for design and especially on issues about what is in the best interest of patients (such as the necessity of placebo controls).

During my time as a patient advocate, we have done our work effectively. I began my advocacy career working on the enactment of the Udall Act for PD Research in 1997 and the NIH PD research agenda in 1999-2000, during this time the scientific research for PD in the Federal government increased from about $50m to $250 but has decreased more recently in a negative Federal budget environment. In 2000 I was patient representative on the DBS advisory Panel at FDA, and subsequently have collaborated with FDA staff to establish, recruit and train Patient consultants to FDA to provide our unique experience as participants in studies and demonstrations (I have participated in nearly 20). Thankfully for our cause, we are blessed with many resourceful comrades in our search for better treatments, including entertainment celebrities, like Michael J Fox, Muhamad Ali, and business leaders like Andy Grove, who have made enormous contributions to fill in many of the gaps in development of therapies.

The problem is in spite of all the accomplishments that we can claim individually or collectively, DBS is the only real breakthrough in PD treatment in the past 40 years Other advances in dopamine replacement therapies have added up to give people more relief from symptoms, but a growing list of failed clinical trials has dampened our hopes for the promised cures.

As our knowledge of genetics and cell functioning, etc. grows the understanding of what we dont know also grows, which puts us further from the goal in the eyes of science than we were at the turn of the century

The most important scientific problem that the PD community faces now is the failure of clinical trials for treatments that we know from 1st hand experience work for some people. As Andy Grove has taught us, we do not want to walk away from the golden nuggets available from failed studies. We have been reading research literature on placebo response and the artificial bias that can result form random assignment to the powerful effects of placebo brain surgery in a clinical trial. We have identified an alternative design based on research on human response to treatments and controlled experiments which is not always the same as animal response to the same situation. This design addresses the short comings of the gold standard design, usually insisted on by FDA.

The "comment" presented below appears on the Alzheimer's Research Forum. It outlines the rationale for our observations. A more detailed presentation with a range of methodological issues important for design of PD studies is being prepared.
-------------------------------------

Comment by Perry D Cohen, PhD:

Don’t Jeopardize New Therapies with Sham Surgery Control – Placebo Responses May Be Part of Therapies.

I was the patient representative on the FDA advisory panel that reviewed deep brain stimulation (DBS) in March of 2000, and later I participated in the Medicare National Coverage decision for DBS on behalf of the requester (not Medtronics but an individual person with Parkinson's). From these engagements, I recall this treatment was shown to be very effective (upwards of 85 percent have 50 percent improvement in motor symptoms). Such dramatic and lasting improvements would need to be expected to offer a treatment that makes it worthwhile to take the risk of brain surgery. After a delay of more than 4 years from the initial advisory group, DBS has been available to patients, as a near breakthrough option once first-line treatment fails. Indeed it is the only major new therapy for PD in the 40 years since levodopa was discovered. Now the recent study published in JAMA continues to show efficacy and also shows that its adverse side effects for important functions like cognition are greater for DBS than with standard drug therapy. The DBS experience can be instructive for other surgical treatments for PD

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 6 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 attribute 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, produces a greater placebo effect. 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' 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 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. 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.

New directions for the 21st century

As science progresses, we need to re-examine our assumptions about the standards for evidence in the assessment of safety and effectiveness. The gold standard of the randomized, prospective, double-blind placebo-controlled study cannot be applied as a one-size-fits-all to conditions on the cutting edge of medical science.

Medical miracles of the 20th 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 neuro-protection.

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.

Continuing failure of studies based on faulty assumptions about human behavior is not a viable option. A better understanding of placebo responses in the design of clinical trials points to new approaches in collaboration with patient advocates and communications to FDA.

Perry D Cohen, PhD directs the Parkinson Pipeline Project: http://www.pdpipeline.org/aboutus/community.htm

Thanks Debi, I was asking that question precisely for the reasons you stated. If Dopamine is what might be involved in Placebo effect, how can one do a controlled clinical trial for PD? Are longitudinal studies better for PD? Each patient serves as his or her own control for whatever parameters tested in the clinical trial. I am not too familiar with clinical studies design and just thinking aloud. Any thoughts on alternative controls to replace placebos in clinical trials?

Girija

QUOTE=Debi Brooks;467738]Again, not an expert but I've heard this discussed frequently in scientific meetings and two bits that come up regularly that might be of interest...

placebo is a biological effect and is found in all sorts of diseases/interventions...it does seem to be particularly vexing in PD...why? the placebo is believed to occur in some part due to triggers in the reward system in the brain--guess which chemical? dopamine. So, in a clinical intervention that actually targets the dopamine system directly or even peripherally, such as many treatment strategies in PD, you have the extra confounding effect. I think there is data that suggests placebo effect can linger particularly long in PD too (many years after intervention).

Debi[/QUOTE]

Girija, I think you mentioned length of trial - maybe the trials aren't long enough. PRECEPT was halted after I'd been in it for 2 years - and I was SUPPOSED to have been in it for 3 years. I can't list many recent trials that have gone that long.

And Debi, if you are right that the placebo effect may last over a year, then it seems logical to me that PD trials should be set up for longer periods.

all that is left is effect of different dosages, and Jean's post bears testimony to the accuracy of that.

The placebo effect can be diluted by greater number of trialists but as we saw with the never ending Spheramine trials, it is hard enough to get existing required numbers.

Perhaps the only answer is to accept placebo, and allow a wider degree of pass/fail for a trial. Given that PD is currently non treated in the advanced stage, what have we got to lose by taking a treatment (e.g. Ceregene), that worked for some and not others. I know there are commercial issues around authorising use of drugs that fall below the FDS's normal pass criteria but in the case of PD, where we cannot even diagnose it more accurately than by crude clinical observation, perhaps the same latitude should be applied to treatment as to diagnosis.

Neil.

p.s. when i see a thread as learned as this with so much relevant and informed comment, it reminds me why i have visited BT2 these past 4 years.

While the medical community considers the placebo effect "particularly vexing" and "this extra confounding effect," as a patient/client/consumer/customer and clincal partner at a great research institution, having participated in about a dozen studies," I believe we can use placebo to our advantage. For several years I have privately believed that if I could get better because I thought a study was of benefit to me, then I could get better because I decided to get better. Unless my extremely competent doctors are flattering me, (an effect as yet unmeasured, LOL), I have gotten better, in important ways, despite the progression of my physical symptoms, and even they have improved at times.

Let us, for example, find a really competent clinical neuropsychologist who specializes in Parkinson's Disease to analyze the data on placebo and coach us in how to decide to get better and to keep the faith (hmmm) until we do.

Thanks to all for the discussion.

Jaye

.

omitted beginning - too analytical and unnecessary verbage

Carolyn has a virus in her computer but will try to get on one tomorrow. She has many questions about her seizure, but now suspects that even with the treatment, she was experiencing the placebo effect.


I have some thoughts/questions to consider:

Are these issues [sham surgery utilities and ethics and placebo effect] a top priority, not by choice, but through necessity, if we ever want to see innovation start flowing thru the pipeline?

Is there danger that the economic disaster will create havoc in our research world?

Do you see a pattern of dragging out certain trials, CoQ10 for ex.,with regard not given to how long it takes? Could this placebo problem be 'further study is needed' for the next several years?

As Jaye mentioned, can we figure out how to use it?

Can research be combined and collaboration expanded among each lab working on similar research? only the big names and universities get the big money-can smaller research labs of similar nature be networked into the process to share what they have learned? is everything being covered that is needed?

i don't expect answers to all of these....but discussion sure welcomed.

thanks all,
paula

All these issues/questions are legit...the challenge is what do you do about sorting out next steps ... and until you do, can you justify going back into humans?

Just a quick and dirty jotting of notes here...in italics, each question raised by Paula (I didn't think they were too analytical) points to areas of need for additional thinking/investment. Which of course means time and money=> delays...very frustrating I know.

1. we don't know if ceregene works well, the trial didn't meet endpoints but does that mean trophic factors aren't worthy of continued emphasis? In my mind, its worth additional work to sort that out and MJFF is working on this. Also, begs the continued emphasis on improving trial design and tools (patient recruitment, biomarkers, etc)--again another priority area for us.

2. there is enough evidence to justify continuing the study ...not continuing the phase II it's done . But, is there a clear path forward and some reasonable probability of success so that Ceregene backers will re-up? That is an important question and a small biotech like Ceregene sometimes doesn't get the luxury of time when the VC clock is ticking.

3. placebo effect - what is real? what is noise? what to do with it? It's real but unpredictable. Some trials see it and others don't...really wasn't there in the Amgen GDNF phase II for instance. Also, its not clear we have to solve the mystery and eliminate placebo (because that could be impossible)...maybe just learn how to predict and structure trials more overtly with placebo in mind. (Just as we recruit 10% additional patients into trials now to account for the fact that we expect noise in the data since we can't definatively diagnose and some trial participants don't actually have PD). But, I believe that this particular connumdrum could be a deterent to investment and that is bad news.

4. target needs to be modified - learned through autopsy Unintended information that is very valuable but still requires a step back to animal models to resolve issues around axonal transport etc. so not immediately back into humans.

5. dosage can be modified [this has been learned concurrent to the trials] Again, back to animals for efficacy and maybe better modelling of volumes/mass difference in primate vs. human brains for better predictability plus dramatic changes in doses might trigger the need for additional safety tests.

6. do less advanced patients need to be used? Phase I and now phase II safety profile will be helpful in making the case but current practice is that high-risk procedure should be reserved for mid to late-stage patients. Certainly the concept of neuron revival makes more sense the earlier in disease process you are able to start the intervention so there is definitely a disconnect here that is hard to resolve.

7. subtypes Not convinced it is particularly glaring in the Ceregene trial / more stage of disease than tremor dominant vs. gait/postural instability but better understanding and validation of subtypes is very important and interesting work continues on many fronts.

8. sham surgery - taking a long hard look at utilities and ethics that can only be productive in this type of conversation? Already covered in this thread.

Anyway, like so many topics...the issues are complex and multifaceted but please know that they are actively discussed at MJFF meetings.

Debi Brooks