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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 > > ---------------------------------------------------------------------- > To sign-off Parkinsn send a message to: mailto:[log in to unmask] > In 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 > ---------------------------------------------- This mail sent through http://www.ukonline.net ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn