Ethics in Clinical Trials
Ethical Standards in Phase 1 Trials of Neuroprotective Agents for Stroke Therapy
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.
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.