I think your letter and your ideas are excellent.  Keep repeating them like a broken record until more people pay attention.  I intend to.

Virginia Schwinge


-----Original Message-----
From: Greg Wasson <[log in to unmask]>
To: [log in to unmask]
Sent: Sun, 6 Jul 2008 11:40 pm
Subject: Spheramine - Another Promising "Failure": Is It Time Reassess Clinical Trial Design?



Hi All,
Has it occurred to anyone else that there may be an important pattern in the
eemingly unbroken string of failures of very promising new PD therapies to
ake it past stage 2 clinical trials? In the GDNF trials, in the recently
iscontinued trials of Spheramine, in the Neuroimmunophilin Ligand trials a few
ears back, in fact in the forty years since the development of the gold
tandard of carbidopa/levodopa, there have been a remarkable number of trials
hat appeared to have dramatic results on patients in early clinical stages but
ubsequently failed to meet statistical endpoints in placebo-controlled
ouble-blind phase 2 trials. 
Could anyone who had seen PWP Peggy Willocks in 2000 before her Spheramine
urgery doubt in any way that her surgery had a dramatic and lasting positive
ffect on her ability to function. Does anyone doubt that the film of some of
he GDNF clinical trial participants before and after receiving that biologic
howed clearly that some of them responded in a way that could not be
ttributable to a placebo response? 
Could it possibly be that some patients are legitimately responding in a
ramatic fashion to these experimental therapies, while others are not,
egardless of the presence of placebo controls? Is it possible that the reason
or these apparently topsy-turvy, now-you-see-it-now-you-don't results are
hemselves the result of clinical trials which are fundamentally flawed in
heir design. That is, if "idiopathic Parkinson's disease" is in fact a bundle
f related diseases as has been increasingly discussed, and may well be a
isease, or diseases, which affects many more parts of the brain than had
raditionally been assumed, it may well be that it's not the data that is wrong
n recent clinical trials, it is the square peg of data which scientists are
rying to fit the into what they refuse to recognize as the round hole of
urrent clinical trial design.
A child can see that the symptoms from patient to patient very so dramatically
hat one would intuitively assume that he or she was looking at different
iseases. How do we make the leap to the assumption that despite the evidence
f our eyes, we all have (with rare exceptions) "idiopathic Parkinson's
isease"? It is rather ironic that this so-called “designer disease” can only
e diagnosed through clinical observation. Clinical observation alone would
ead the average person to assume that more than one disease, or form of the
isease, is present in the population. But since the discovery that
arbidopa/levodopa dramatically ameliorates the symptoms of PD in almost all
atients regardless of their presenting symptoms, and because we can detect a
ramatic loss of dopaminergic cells in "PD" patients through brain scans and at
utopsy, we leap to the conclusion that we all suffer from the exact same
alady.
It seems to me that the existence of several variants on what we call one
isease would explain the varying results or effects on patients with regard to
ew experimental therapies. We know so little about the disease in the larger
ense that we even call it "idiopathic," meaning of unknown origin. Remember,
nly a few short years ago, even a movement disorder specialist would have told
ou that Parkinson's, in an oft-repeated comparison, was the disease that left
our mind clear while trapping you in a body that would eventually lave you
ompletely immobilized, while Alzheimer's was the disease that destroyed your
ind while leaving your body intact. I don't think that any movement disorder
pecialist worth his or her credentials would make that same statement today
bout Parkinson's disease. We know that it affects frontal cortex to some
egree in almost every patient. And it appears to affect other areas of the
rain as well. Could it be that we have been so mesmerized for the last 190
ears by the massive and dramatically observable destruction that Parkinson's
oes to the portion of the brain devoted to movement that we failed to
ecognize what in hindsight should have been obvious secondary symptoms of the
isease or a set of related diseases?
We all know that a new paradigm of Parkinson's disease is emerging that in some
ays is consistent with the view of Parkinson's I have described above. What we
ill finally learn about Parkinson's and its causes, and the dramatic variance
f symptom constellations among individual patients, remains to be seen. But I
hink that it's time to take a good hard look at clinical trials and their
esults in light of this emerging new view of what we had assumed was a single
isease. If Parkinson's is indeed a cluster of related diseases it would make
ense that some therapeutic applications would work for all or nearly all of
he patient population, such as carbidopa/levodopa. It would also make sense
hat certain dopamine agonists would work among a large portion of the
opulation, but leave a significant minority of patients unaffected or with a
egative response to the therapy.
Perhaps most importantly, it would explain why year after year, decade after
ecade, we have been getting to large phase 2 trials and winding up with
tatistical endpoints that may in fact be unachievable for most therapeutic
pplications because only certain patients with certain variants of the disease
re going to respond. It may be that bad trial management in some cases
disconnected catheters and poor infusion techniques in the GDNF trials) and
lacebo effect itself are "noise" that interferes with a proper interpretation
f what these drugs are doing to patients. A proper interpretation of this
attern of clinical trial failures may mean having to conclude that the trial
esign itself is based on the false premise that we all have the same variant
f the same disease.
As PWP and Intel founder Andy Grove has asked, why aren't we learning from our
ailures? Why do we keep coming at the same problem from the same position with
he same set of assumptions? Why don't we at least entertain the notion that
he way we test new therapies is inconsistent with the disease, or diseases,
hat we are trying to cure. In fact, one would almost think that the refusal to
udge from the current thinking about Parkinson's clinical trials reflects some
f the cognitive damage that Parkinson's does in the tendency of patients to
xhibit a stubborn inability to move from one approach to another. All the
hile, we may be throwing away the baby with the bathwater, as therapy after
herapy that may in fact address major problems for some of the patient
opulation, are deemed to be failures and tossed aside. If so, it is a mistake
f gigantic proportions, and one which has tremendous significance for us all.
I hope I haven't stated the obvious, or shown my ignorance of clinical trial
esign and biomedical science, but when I advanced this idea at a PD meeting
wo weeks ago, I looked across the room at a top British neuroscientist who
odded his head "yes" the entire time I was speaking. Interestingly, however,
e remained silent.
Just thinking out loud,
Greg
----------------------------------------------------------------------
o sign-off Parkinsn send a message to: mailto:[log in to unmask]
n the body of the message put: signoff parkinsn


----------------------------------------------------------------------
To sign-off Parkinsn send a message to: mailto:[log in to unmask]
In the body of the message put: signoff parkinsn