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.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
- Copyright © 1998 by American Heart Association
Slyter H. Ethical challenges in stroke research. Stroke. 1998;29:1725–1729.
Marler JR, Walker MD. Progress in acute stroke research. Stroke.. 1998;29:1491–1492. Editorial.
NINDS rt-PA Stroke Study Group. Response to ethical challenges in stroke research Stroke. 1998;29:1492–1493. Editorial.
Albers GW, Ziven JA, Choi DW. Ethical standards in phase 1 trials of neuroprotective agents for stroke therapy. Stroke.. 1998;29:1493–1494. Editorial.
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.
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.