Quite - how can you fix the problem till you've found the cause ?

Quoting rayilynlee <[log in to unmask]>:

> Greg
> 
> This is why I worry about a one-size-fits-all  "cure" that works for 
> everyone.  I don't believe the causes of this disease/s are understood at 
> all.
> 
> Ray
> Rayilyn Brown
> Director AZNPF
> Arizona Chapter National Parkinson Foundation
> [log in to unmask]
> ----- Original Message ----- 
> From: "Greg Wasson" <[log in to unmask]>
> To: <[log in to unmask]>
> Sent: Sunday, July 06, 2008 8:40 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
> seemingly unbroken string of failures of very promising new PD therapies to
> make it past stage 2 clinical trials? In the GDNF trials, in the recently
> discontinued trials of Spheramine, in the Neuroimmunophilin Ligand trials a 
> few
> years back, in fact in the forty years since the development of the gold
> standard of carbidopa/levodopa, there have been a remarkable number of 
> trials
> that appeared to have dramatic results on patients in early clinical stages 
> but
> subsequently failed to meet statistical endpoints in placebo-controlled
> double-blind phase 2 trials.
> 
> Could anyone who had seen PWP Peggy Willocks in 2000 before her Spheramine
> surgery doubt in any way that her surgery had a dramatic and lasting 
> positive
> effect on her ability to function. Does anyone doubt that the film of some 
> of
> the GDNF clinical trial participants before and after receiving that 
> biologic
> showed clearly that some of them responded in a way that could not be
> attributable to a placebo response?
> 
> Could it possibly be that some patients are legitimately responding in a
> dramatic fashion to these experimental therapies, while others are not,
> regardless of the presence of placebo controls? Is it possible that the 
> reason
> for these apparently topsy-turvy, now-you-see-it-now-you-don't results are
> themselves the result of clinical trials which are fundamentally flawed in
> their design. That is, if "idiopathic Parkinson's disease" is in fact a 
> bundle
> of related diseases as has been increasingly discussed, and may well be a
> disease, or diseases, which affects many more parts of the brain than had
> traditionally been assumed, it may well be that it's not the data that is 
> wrong
> in recent clinical trials, it is the square peg of data which scientists are
> trying to fit the into what they refuse to recognize as the round hole of
> current clinical trial design.
> 
> A child can see that the symptoms from patient to patient very so 
> dramatically
> that one would intuitively assume that he or she was looking at different
> diseases. How do we make the leap to the assumption that despite the 
> evidence
> of our eyes, we all have (with rare exceptions) "idiopathic Parkinson's
> disease"? It is rather ironic that this so-called "designer disease" can 
> only
> be diagnosed through clinical observation. Clinical observation alone would
> lead the average person to assume that more than one disease, or form of the
> disease, is present in the population. But since the discovery that
> carbidopa/levodopa dramatically ameliorates the symptoms of PD in almost all
> patients regardless of their presenting symptoms, and because we can detect 
> a
> dramatic loss of dopaminergic cells in "PD" patients through brain scans and
> 
> at
> autopsy, we leap to the conclusion that we all suffer from the exact same
> malady.
> 
> It seems to me that the existence of several variants on what we call one
> disease would explain the varying results or effects on patients with regard
> 
> to
> new experimental therapies. We know so little about the disease in the 
> larger
> sense that we even call it "idiopathic," meaning of unknown origin. 
> Remember,
> only a few short years ago, even a movement disorder specialist would have 
> told
> you that Parkinson's, in an oft-repeated comparison, was the disease that 
> left
> your mind clear while trapping you in a body that would eventually lave you
> completely immobilized, while Alzheimer's was the disease that destroyed 
> your
> mind while leaving your body intact. I don't think that any movement 
> disorder
> specialist worth his or her credentials would make that same statement today
> about Parkinson's disease. We know that it affects frontal cortex to some
> degree in almost every patient. And it appears to affect other areas of the
> brain as well. Could it be that we have been so mesmerized for the last 190
> years by the massive and dramatically observable destruction that 
> Parkinson's
> does to the portion of the brain devoted to movement that we failed to
> recognize what in hindsight should have been obvious secondary symptoms of 
> the
> disease or a set of related diseases?
> 
> We all know that a new paradigm of Parkinson's disease is emerging that in 
> some
> ways is consistent with the view of Parkinson's I have described above. What
> 
> we
> will finally learn about Parkinson's and its causes, and the dramatic 
> variance
> of symptom constellations among individual patients, remains to be seen. But
> 
> I
> think that it's time to take a good hard look at clinical trials and their
> results in light of this emerging new view of what we had assumed was a 
> single
> disease. If Parkinson's is indeed a cluster of related diseases it would 
> make
> sense that some therapeutic applications would work for all or nearly all of
> the patient population, such as carbidopa/levodopa. It would also make sense
> that certain dopamine agonists would work among a large portion of the
> population, but leave a significant minority of patients unaffected or with 
> a
> negative response to the therapy.
> 
> Perhaps most importantly, it would explain why year after year, decade after
> decade, we have been getting to large phase 2 trials and winding up with
> statistical endpoints that may in fact be unachievable for most therapeutic
> applications because only certain patients with certain variants of the 
> disease
> are going to respond. It may be that bad trial management in some cases
> (disconnected catheters and poor infusion techniques in the GDNF trials) and
> placebo effect itself are "noise" that interferes with a proper 
> interpretation
> of what these drugs are doing to patients. A proper interpretation of this
> pattern of clinical trial failures may mean having to conclude that the 
> trial
> design itself is based on the false premise that we all have the same 
> variant
> of the same disease.
> 
> As PWP and Intel founder Andy Grove has asked, why aren't we learning from 
> our
> failures? Why do we keep coming at the same problem from the same position 
> with
> the same set of assumptions? Why don't we at least entertain the notion that
> the way we test new therapies is inconsistent with the disease, or diseases,
> that we are trying to cure. In fact, one would almost think that the refusal
> 
> to
> budge from the current thinking about Parkinson's clinical trials reflects 
> some
> of the cognitive damage that Parkinson's does in the tendency of patients to
> exhibit a stubborn inability to move from one approach to another. All the
> while, we may be throwing away the baby with the bathwater, as therapy after
> therapy that may in fact address major problems for some of the patient
> population, are deemed to be failures and tossed aside. If so, it is a 
> mistake
> of 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
> design and biomedical science, but when I advanced this idea at a PD meeting
> two weeks ago, I looked across the room at a top British neuroscientist who
> nodded his head "yes" the entire time I was speaking. Interestingly, 
> however,
> he remained silent.
> 
> Just thinking out loud,
> 
> Greg
> 
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