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From the Department of Neurology, University of Virginia Health System,
Charlottesville, Va.
Correspondence to E. Clarke Haley, Jr, MD, Box 394, Department of Neurology, University of Virginia Health System, Charlottesville, VA 22908. E-mail ech{at}virginia.edu
Dr
Slyter1 raises a number of important points.
Investigational drug trials are ultimately the result of a complex
scientific and ethical balancing act very familiar to the investigators
involved in the studies that Dr Slyter cites. It is unfortunate that
new treatments cannot be developed without risk, but we do not believe
that the principle of "do no harm" should be translated into
"make no attempt to help unless risks can be eliminated." Virtually
all forms of treatment involve risks. A physician's role is to try to
assess the benefit-to-risk ratio. Most commonly accepted therapies can
have side effects ranging from serious injury to death, and many
patients do not respond to a given form of treatment. If avoiding harm
was the only objective of physicians, it would be a logically
defensible position that we should not treat anyone.
The purpose of a phase 1 trial is not to prove the efficacy of a new
agent, and one can predict with near certainty that some patients will
suffer adverse events. This is inevitable in almost any drug
development program, because the tolerability limits of a new form of
treatment must be explored to define its safety profile. Initial
estimates are derived from preclinical testing, but the final
determination must come from human studies. It is not more ethical to
expose healthy volunteers to potential side effects than to conduct
these trials in patients who have at least the possibility of benefit
from the investigational agent. The safety problems encountered in
phase 1 acute stroke trials do not fundamentally differ from previous
drug development programs for a wide variety of illnesses. Concern for
patient safety dictates the deliberate and careful dose-escalation
study design. Stroke is a particularly catastrophic disease, and it is
within ethical bounds to expect that some patients in an acute stroke
trial might suffer severe adverse effects.
The potential for drug-induced injury must be explained to prospective
study patients in a manner that is specified and approved in advance of
the trial. These plans are reviewed by institutional review boards
(IRBs) that include physicians who are not directly involved in the
clinical testing, as well as other patient advocates. It is, however,
impossible to inform patients fully of the risk-benefit ratio during a
drug development trial, since that information is derived ultimately
from the entire drug development process. If a patient does not wish to
assume unknown risks, he or she can simply refuse to participate in a
trial, and many do. Although the need for rapid decisions in acute
stroke trials increases the possibility that a patient will not be
adequately informed, the expanded enrollment windows chosen for phase 1
trials afford additional time for discussion of risks versus potential
benefits. Additional safeguards include FDA and IRB scrutiny of the
protocol prior to initiation, the requirement that adverse events be
reported to both the FDA and IRBs in a timely manner during the course
of a trial, and assurance that the study will be terminated or modified
if predetermined safety limits are exceeded.
A number of recent acute stroke studies, including the dextrorphan
trial, were terminated because potential benefits did not exceed the
adverse events by a sufficient margin. This is evidence of the system
working properly. No ethical physician wants to imperil a patient, but
choosing to do nothing exposes the patients to well-known risks and no
possible benefit. Development of new forms of therapy exposes patients
to uncertain risks along with possible benefits.
In reference to the dextrorphan trial, Dr Slyter expresses two major
concerns. First, he believes the number of patients who suffered
potentially harmful episodes of hypotension was excessive and suggests
that dose-escalation studies should "carefully titrate doses upward
and stop when dose-limiting events are encountered." In fact, this is
exactly the approach used in the dextrorphan trial. The study was begun
in early 1991 and proceeded cautiously over the next 2 years. Six
protocol modifications, each individually approved by the IRB at every
participating hospital, were made during the course of the trial. Nine
different dose groups were studied (typically with 6 patients per
group). Data from each dose group were carefully evaluated prior to
proceeding to the next dose group. In dose group VIII, 5 patients
received a 260-mg loading dose of dextrorphan. Two of these 5 patients
suffered transient, rapidly reversible, hypotensive events during the
loading dose. One patient's hypotensive event occurred immediately
after receiving compazine, and the other patient had received
verapamil 1 hour before initiation of the dextrorphan
infusion. Therefore, it was unclear whether the hypotensive episodes
were caused by dextrorphan or concomitant medications. However, because
of these events, the planned dose escalation was halted, and the
protocol was modified to allow additional patients to be enrolled at
the 260-mg loading dose. Six additional patients were enrolled. Three
of these had hypotensive events (2 of the 3 immediately following
treatment with compazine). In all cases, the hypotension was rapidly
reversible, and none of the patients had any detectable worsening of
their neurologic status. However, because of safety concerns, the next
protocol amendment called for a reduction in the loading dose in hopes
of avoiding any hypotensive events. Ten additional patients were
enrolled at a loading dose of 200 mg. Two of the 10 patients suffered
brief hypotensive events unassociated with clinical worsening. At this
point, the trial was terminated.
Dr Slyter's other major concern about the dextrorphan trial is that an
NMDA antagonist could not have beneficial events in humans
if administered many hours after the onset of stroke symptoms. This
conclusion is unjustified. Data from animal models of stroke have
established the principle of a "therapeutic window": that these and
other classes of neuroprotective drugs can reduce ischemic
infarction even when administered in a delayed fashion, well after the
onset of brain ischemia. As Dr Slyter notes, the duration of
this therapeutic window in animal models has been typically 1 to 3
hours, but in these models, cerebral vessels are artificially occluded
to produce a synchronized ischemic insult, maximal at onset. In
human stroke, symptoms not uncommonly can stutter or progress over
time, most likely reflecting changes in the ischemic insult
itself. Thus in humans, unlike most experimental stroke models, some
brain regions may undergo initial ischemia many hours after the
initial onset of symptoms. And even in situations where
ischemia does not progress topographically, there are
sufficient differences in vascular or cerebral biology between humans
and animals that a direct quantitative extrapolation of therapeutic
window duration across species is not scientifically sound.
Dr Slyter is pleased that "the era of nihilism in stroke in
thankfully over." How did this happen? It required the dedication of
a large number of physicians and nurses, support from the federal
government and pharmaceutical companies, and patients and their
families who were courageous enough to participate.
The issues raised by Dr Slyter are very important and deserve
continuing scrutiny. However, we do not believe that the physicians and
IRBs involved in the trials he questions fell below the highest ethical
standards. It is easy to be critical of therapeutic failures, but in
balance, many stroke victims now have the possibility of benefiting
from proven medical and surgical interventions. Much better treatments
for stroke are needed, and continued clinical investigations are the
only way to develop these improvements.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Since publication of the results of the NINDS rt-PA Stroke Trial, several members of the NINDS rt-PA Stroke Study Group have participated in a Genentech Speakers' Bureau and have received honoraria for their work. No conflicts of interest existed, however, during the conduct of the NINDS rt-PA Stroke Trial, sponsored by the NINDS, which is referenced in this editorial response.
References
1.
Slyter H. Ethical challenges in stroke research.
Stroke. 1998;29:1725–1729.
2.
Marler JR, Walker MD. Progress in acute stroke
research. Stroke.. 1998;29:1491–1492. Editorial.
3.
NINDS rt-PA Stroke Study Group. Response to ethical
challenges in stroke research Stroke. 1998;29:1492–1493.
Editorial.
4.
Albers GW, Ziven JA, Choi DW. Ethical standards in
phase 1 trials of neuroprotective agents for stroke therapy.
Stroke.. 1998;29:1493–1494. Editorial.
5.
Brott T, Lu M, Fagan S, Kothari R, Frankel M, Grotta
JC, Broderick J, Kwiatkowski T, Lewandowski C, Haley EC, Marler JR,
Tilley BC, for the NINDS rt-PA Stroke Study Group. Hypertension and its
treatment in the NINDS rt-PA Stroke Trial. Stroke. 1998;29:1504–1509.
6.
Federal Register, Part III, Department of Health, and
Human Services, Food, and Drug Administration. 21 CFR Part 30 et al,
Protection of Human Subjects; Informed Consent; Proposed rule,
Thursday, September 21, 1995.
7.
The National Institutes of Neurological Disorders and
Stroke rt-PA Stroke Study Group. Tissue plasminogen
activator for acute ischemic stroke. N
Engl J Med. 1995;333:1581–1587.
© 1998 American Heart Association, Inc.
Editorials
Ethics in Clinical Trials
Response to Ethical Challenges in Stroke Research
Key Words: clinical trials • editorials • ethics
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  G. W. Albers, J. A. Zivin, and D. W. Choi Ethics in Clinical Trials : Response to Ethical Challenges in Stroke Research Stroke, August 1, 1998; 29(8): 1492 - 1493. [Full Text]
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G. W. Albers, J. A. Zivin, and D. W. Choi Ethics in Clinical Trials : Ethical Standards in Phase 1 Trials of Neuroprotective Agents for Stroke Therapy Stroke, August 1, 1998; 29(8): 1493 - 1494. [Full Text]
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J. R. Marler and M. D. Walker Ethics in Clinical Trials : Progress ni Acute Stroke Research Stroke, August 1, 1998; 29 (8): 1491 - 1492. [Full Text]
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