Opinion: Is there an important pattern in the seemingly
uninterrupted failure of drugs and biologics?
By Greg Wasson
July 6, 2008
Has it occurred to anyone else that there may be an important pattern in the seemingly uninterrupted failure of drugs and biologics showing great promise for Parkinson's disease in early clinical trials to make it to the finish line? In the GDNF trials, in the trials recently discontinued with Spheramine, 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 which failed to meet statistical endpoints in placebo-controlled double-blind phase II or III trials.
Could anyone who had seen Spheramine trial participant Peggy Willocks in 2000 before her surgery doubt in any way that her procedure 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 which 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, it may be that it's not the data that is wrong in recent clinical trials; it is that scientists keep trying to fit the square peg of data from Parkinson's trials into a round hole of inappropriate clinical trial design.
A child can see that the symptoms from patient to patient vary so dramatically that one would intuitively assume that we are looking at different diseases. How do we make the leap to the assumption that despite the evidence of our eyes, we all have (with some 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 same exact 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 the often repeated comparison, was the disease that left your mind clear while trapping you in a body that was eventually 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 to some degree in almost all patients the frontal cortex. And it appears to affect other areas of the brain as well. Could it be that we have been so mesmerized for the last 200 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 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 that I have outlined 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 among all or nearly all of the patient population, such as in most, but not all cases, 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 for 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 Andy Grove stated during his speech at the Society for Neuroscience in 2007, 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(s), 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 thrown away. If so, it is a mistake of gigantic significance for us all.
I hope I haven't stated the obvious, or showed my ignorance of clinical trial design and biomedical science, but when I advanced this idea at a recent PD meeting, I looked across at an English neuroscientist who nodded his head "yes" the entire time I was speaking. Interestingly, however, he remained silent.
Just thinking out loud, Greg Wasson
Parkinson’s Action Network (PAN) Senior Advisor – Legislation;
Received first PAN Millicent Kondracke Award for Outstanding Advocacy - 2002
Parkinson Pipeline Project
World Parkinson Congress 2010 Patients Advisory Committee
Diagnosed in 1995
See list of terminated treatments