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May 24, 2006

GDNF poses troubling questions for doctors and drug maker

Opposing Viewpoints on GDNF for Parkinson’s

Doctors involved in the Phase I and Phase II clinical trials of GDNF expressed their opposing views of the trial halt by Amgen in current issues of the journal Annals of Neurology.

The March 2006 issue of Annals of Neurology contained an unsigned article in the NerveCenter (news) section supporting the halt and questioning the conduct of the successful Phase I trials and the expertise of those investigators to carry out the clinical trial. The article also questioned whether the judgment of some of the trial doctors was compromised by being “too close” to their patients. Although the article in unsigned, Dr. Tony Lang (Phase II lead investigator) is heavily quoted. Phase I trial researchers from the Udall Parkinson’s Center of Excellence at the University of Kentucky took exception to these charges and responded in a letter published in the June 2006 issue of Annals. Excerpts from both the NerveCenter article and the responding letter follow.

“GDNF Poses Troubling Questions for  Doctors, Drug Maker”
Anonymous. Annals of Neurology. March 2006, A5-6.

Excerpts:
“Two new articles about glial cell-derived neurotrophic factor (GDNF; one in this issue of the Annals of Neurology, the other in the February issue of Movement Disorders—address the rocky interface between the need for evaluating new drugs with caution and the hopes and expectations of patients afflicted with a devastating, progressive, and incurable disease. Some would say they also reflect the problems that arise when well meaning physicians identify so closely with their patients that it affects their better judgment.”

“…But the GDNF experience raises broader questions as well. What exactly is the duty of a drug company and its clinical investigators to participants in clinical trials? “We inform patients up front that the investigator or the sponsor has the right to terminate the study at any time,” Dr. Lang told NerveCenter. Nevertheless, he said, when a clinical trial involves invasive surgery and close, prolonged observation, patients tend to develop very profound hopes. It’s up to the principal investigators to keep the patients’ expectations grounded in reality.
That brings up a second caveat: investigators must be familiar with the disease involved. “This experience emphasizes the importance that the participating physicians be expert in the disorder they are studying,” Dr. Lang maintained. “When one is developing novel therapies and working with a preliminary evaluation of the issues, the clinicians and their center should have experience with the disorder and its variability.”

“…A third issue concerns the fear among drug companies that one false step may lead to litigation. After the $253 million verdict returned against Merck over its COX-2 inhibitor, Vioxx, last summer, companies can hardly be faulted for erring on the side of caution, especially when the most rigorous trial to date has produced negative results. Should a
company give in to patients’ pleas that it continue to provide a new drug when a double-blind study yields negative results, and when toxicity studies yield findings whose implications are unknown?
“We don’t even know what endogenous GDNF does in the adult human brain,” Dr. Lang said. “It seems a little extraordinary to pretend this is not a safety issue.”

“Reply to GDNF Poses Troubling Questions for Doctors, Drug Maker”
John T. Slevin, Greg A. Gerhardt, Charles D. Smith, Don M. Gash, A. Bryon Young.
Annals of Neurology, June 2006, 989-90.

“This article implies that physicians in our and another small unblinded trial were well meaning in their intent, but too close to their patients, and thereby clouded in their clinical judgment. The article further implies that the investigators in these two trials might have been inexperienced in Parkinson’s disease (PD), and thus unable to appreciate variability in the expression of the disease or the strength of placebo effects. These issues were raised perhaps to explain the positive results in both trials... “

The authors rebut these implications, noting that: The University of Kentucky Movement Disorder Center has “the greatest direct clinical experience with intraputamenally delivered GDNF of any center in North America,” and has participated in clinical trials of PD for over a decade.

Their faculty members are well qualified and experienced in designing and conducting clinical trials.

They consider possible toxicity issues to be of prime importance and have been carrying out follow up studies on both the monkeys and human trial participants to determine if antibodies and brain lesions are indeed safety issues for GDNF treatments. They have published journal articles on this topic.

“We continue to monitor our patients and have published the only study that analyzes the potential effect of GDNF on cerebella of exposed humans. Our Udall Parkinson’s Disease Research Center of Excellence is actively engaged in the evaluation of cerebellar toxicity in GDNF-exposed monkeys, as requested by the director of the National Institute of Neurological Disorders and Stroke, National Institutes of Health.”

The Kentucky doctors met with the FDA to discuss resuming extended treatments for the current trial participants and “there was an opportunity for compassionate use, which unfortunately was not implemented by the patent holder” (Amgen)

“There was much in the article to commend regarding the identification of problems in GDNF trials, but the gratuitous and unhelpful nature of some of the statements, as well as the lack of critical comment regarding the reported randomized trial in Annals, made this article unbalanced. That none of the vague statements is documented or demonstrably true raises our ire. … we believe we must protest the one-sided nature of the comments in this Annals article, in particular, because it appeared without proper balance in a premier forum before our peers.”

The Parkinson Pipeline Project has been studying this issue extensively since the trial halt in September 2004. We applaud the University of Kentucky doctors for their dedication to their patients, to finding better treatments for Parkinson’s Disease and for their courage in speaking out for what they know is right.

 


References:
Slevin JT, Gerhardt GA, Smith CD, et al. Unilateral intraputamenal GDNF improves bilateral motor functions in patients with Parkinson disease. Journal of Neurosurgy, 2005;102:216 –222.

Chebrolu H, Slevin JT, Gash DM, et al. MRI volumetric and intensity analysis of the cerebellum in Parkinson’s disease patients infused with glial-derived neurotrophic factor (GDNF).Experimental Neurology 2006;198:450–456.

John T. Slevin, M.D., Don M. Gash, PH.D., Charles D. Smith, M.D., Greg A. Gerhrdt, PH.D., Richard Kryscio, PH.D., Himachandra Chebrolu, M.S., Ashley Walton, B.S., Renee Wagner, R.N., and A. Byron Young, M.D. Unilateral intraputaminal glial cell line–derived neurotrophic factor in patients with Parkinson disease: response to 1 year each of treatment and withdrawal. Neurosurgical Focus,Vol.20, May 2006,E1.

Copyright© 2012 Pipeline Project

All rights reserved. Revised: 01/26/12.