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From the Division of Stroke, Trauma and Neurodegenerative Disorders,
National Institutes of Health, National Institute of Neurological Disorders
and Stroke, Bethesda, Md.
Correspondence to John R. Marler, MD, Division of Stroke, Trauma and Neurodegenerative Disorders, NIH, NINDS, Room 8A08, Federal Building, 7550 Wisconsin Ave, Bethesda, MD 20892. E-mail marlerj{at}ninds.nih.gov
We are delighted to
respond to Dr Slyter's1 commentary on acute
stroke research. At the outset, we would like to state that stroke
research is critically important for improving the health of the
public, that many important clinical questions cannot be answered
without clinical trials, and that the NINDS and stroke investigators
are committed to protecting those who choose to participate in clinical
research. Dr Slyter voices specific concerns about early phase 1
studies that offer no therapeutic benefit to the patient. He is also
concerned about how to treat patients assigned to the control group in
a randomized trial when there is widespread controversy about standard
care, which may be as much a medical issue as an ethical one.
Dr Slyter questions the management of blood pressure in the NINDS rt-PA
Stroke Trial. In fact, management of blood pressure in the trial was
designed with careful consideration of the patients in both the placebo
and active treatment arms of the trial. The reader may wish to read the
references concerning the treatment of blood pressure cited by Dr
Slyter. As he himself states, there is very little data and a great
deal of controversy regarding this issue. Physicians must form their
own opinions after reading the reports he cites in support of his
arguments. In addition, in this issue of Stroke, the NINDS
rt-PA Stroke Trial investigators report on an analysis of data
that will provide the reader with more insight into the limits placed
on the management of blood pressure that was part of the standard care
offered to all patients in that trial.
With regard to patient consent, many of Dr Slyter's comments support
generally accepted principles that are implemented in Federal
regulations. These principles were strictly adhered to in the NINDS
rt-PA trial and continue to be followed in the design of new stroke
research. Institutional review boards today are extraordinarily aware
of the rapidly changing management paradigm for stroke and the
necessity to adequately assess toxicity before, during, and after the
performance of a randomized clinical trial. As Dr Slyter points
out, other questions and recommendations concerning consent to
participate in research have already been addressed by a 1995
modification of Federal regulations that specifically addresses and
clarifies the conduct of clinical research in the emergency treatment
of life-threatening disease.6 The reader is
referred to those regulations and the accompanying summary of extensive
and thoughtful public discussion that occurred before the regulations
were adopted.
We wish to emphasize that Dr Slyter's cautionary comment applies
primarily to those early phase 1 toxicity studies which offer patients
no potential therapeutic benefit despite some significant risk. We
agree with him that these trials, uncommon as they are, require special
consideration by institutional review boards for additional
protections. We do not agree that attempts to find new and better
treatments for acute stroke should cease. Serious life-threatening and
disabling disease warrants taking some risk, especially when there is
some possible benefit for the patient participating in the study.
The successful implementation of the NINDS strategy for the development
of acute stroke treatment is leading to major changes in the
conceptualization and delivery of care to stroke patients. Since 1983,
when the first NINDS acute stroke project was started, the time
window for initiating treatment in clinical studies has dropped from
over 48 hours to less than 3 hours. At the same time, Federal
regulations for human subject research were modified in 1985, 1991, and
again in 1996. As the standards for acute stroke care change so will
the methods of clinical research and likewise the way in which human
subjects are protected from the risks of research. Acute stroke
researchers are acutely aware of the possible risks to human subjects
inherent in the rapid treatment of this serious and life-threatening
disease. They are also becoming aware that doing nothing may entail an
even greater risk.
Many physicians who live by the rule to "do no harm" have serious
ethical concerns about doing nothing just because it is safe and
conservative, particularly in a life-threatening situation. As an
alternative to slowing down the already difficult and complex process
of developing better stroke treatments, we suggest that clinical
researchers, ethicists, and concerned practicing physicians continue to
cooperate to find even better protection for the patients who
participate in clinical research.
We have requested the investigators of the two trials discussed by Dr
Slyter to provide more specific responses. Their comments are
presented below.
While the fundamentals of ethics remain unchanged, the ethical
management of patients, and stroke patients in particular, is
constantly evolving, as we learn more through the scientific process.
It is unfortunate, but true, that progress entails some risk. We
believe that the code of federal regulations, institutional review
boards, peer review, and performance and safety monitoring
boards and investigators are individually and collectively vigilant on
behalf of patient welfare. On the whole, they do an outstanding job. We
would like to invite Dr Slyter to join the academic community, stroke
researchers, and private practitioners in projects that
would help provide more objective information on which to base our
future decisions and actions.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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
Progress ni Acute Stroke Research
Key Words: clinical trials • editorials • ethics
This article has been cited by other articles:
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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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