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.
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