Ask the Ethicist: Should a clinical trial coordinator blow the whistle?

Winter 2004, Vol. 11, Issue 1

Question: A 34-year-old pharmacist entered a multi-institutional, blinded, placebo controlled clinical trial for amyotrophic lateral sclerosis (ALS) in which a drug available by prescription was the active agent. At no time was the patient explicitly told that an attempt to ascertain the contents of the pills that she was taking could be considered a violation of the integrity of the study. During one study visit, she confided to a study technician that she had given one of the pills to a friend to be analyzed. That friend had in turn placed the results of the analysis in a sealed envelope and given it to the patient who stated that she had not opened the envelope. With ambivalence, the study technician informed the principal investigator, torn between respecting the perceived confidence that the patient shared, and the apparent violation of the integrity of the study. How should the principal investigator respond?

Response: Failure to maintain blinded conditions is a common flaw in randomized clinical trials, and a serious criticism of a great many such trials is that the investigators fail to determine how well the blinding is preserved. In many cases, the experimental drug has common, minor side effects, and unless the comparison drug mimics those side effects, it is relatively easy for subjects to guess if they are getting the experimental or the control drug. Indeed some critics have claimed that the entire case for the efficacy of antidepressants rests on this failure to maintain blinded conditions; if one looks only at studies where the investigators documented that double-blind conditions were scrupulously maintained, then antidepressants cannot be shown to be much better than placebo. ¹ I mention this merely to show that one does not have to analyze one's own pills, for the problem of breaking the blind to arise.

Breaking the blind does indeed challenge the integrity of the research study. Fortunately it does so only for this one subject. Therefore, if at the end of the trial, data have to be discarded, they would involve only this one person and one hopes that would not threaten the successful completion of the trial. But that assumes that the blind has been broken, and according to the facts as stated, this has not yet occurred.

If the subject has not yet actually found out what medicine she is receiving, the blind has been preserved. But she must be told that if she wishes to remain in the trial, she must not "open the envelope," and if she does, she is obligated to inform the study team.

I see no reason why the study technician should feel "torn" in this case when one analyzes the ethical duties of all parties. She presumably has no relationship with this person except for her role in the study. She has appeared at this person's doorstep, as it were, solely in her role as a member of the study team. She has no right to any "private" confidences with this woman where matters that impact upon the study integrity are concerned.

The reason the study technician might inappropriately feel a sense of being "torn" points out a common ethical misperception about randomized controlled trials of innovative medications. This misperception has been fueled by a schism within the bioethics literature itself. A portion of that literature takes the view that the clinical practice of medicine and the conduct of clinical research trials are two distinct types of activities, and therefore the ethical principles governing them are also distinct. Another portion of the literature takes the view that all of medicine ought to be governed by the ethical principles of therapeutic practice, and that clinical research is really a subset of practice and so should fall under those same principles.

My position is that the first view is correct. ² The investigator-subject relationship in a research trial is a fundamentally different ethical relationship from the physician-patient relationship in a therapeutic context. The goal of the research enterprise is fundamentally that of discovering new knowledge that will help future patients. The goal of the therapeutic enterprise is fundamentally that of helping each individual patient with the best available remedies.

This example highlights why these goals and relationships are ethically distinct. We presume today that it is virtually never in the best interests of a patient to be denied the knowledge of what medicine she is receiving. The withholding of that information serves the goal of research, not any reasonable goal of therapy. But a person in a clinical trial is not being treated as a patient at all; she is being treated as a research subject. This role is quite appropriate assuming that the conditions of the study, including voluntary informed consent, are not exploitive.

The study technician might assume that she had a therapeutic relationship with this patient and that therefore there was a duty of confidentiality. But no such relationship exists and the technician can report her concerns to the principal investigator with a clear conscience.

It sometimes happens that real-world circumstances cause a blurring of the roles that I have described here as ethically distinct. A neurologist, for instance, may be both the patient's attending physician, and the principal investigator of a study in which the patient is enrolled. I would argue that it is usually desirable to avoid this role conflict, but for various reasons avoidance is not always possible or desirable. When the same physician (and perhaps the office staff) are forced to cross role boundaries, I would argue that it is still highly desirable to think about each encounter with the patient as falling within one role or the other. That is, the technician should remind herself that in this situation the "patient" is really a research subject and not truly a patient, even though in another setting this same individual might be a patient. Some difficulties and gray areas will inevitably arise, but trying to maintain role clarity in one's mind will go a good way toward resolving many ethical problems. ³

Howard Brody, MD, PhD
Professor, Family Practice
Professor, Center for Ethics & Humanities
in the Life Sciences
Michigan State University,
East Lansing, MI

Outcome:

The technician and the principal investigator explained their dilemma to the patient. She stated that she had not opened the envelope, and she was allowed to continue in the study with the caveat that she would be dropped if there was an additional violation. The patient remains enrolled in the trial.

Footnotes

¹ Greenberg RP, Bornstein RF, Greenberg MD, Fisher S. A meta-analysis of antidepressant outcome under "blinder" conditions. J Consult Clin Psychol 1992;60:664-9.

² Miller FG, Brody H. A critique of clinical equipoise. Therapeutic misconception in the ethics of clinical trials. Hastings Cent Rep 2003;33(3):19-28.

³ Brody H, Miller FG. The clinician-investigator: unavoidable but manageable tension. Kennedy Inst Ethics J 2003;13:329-46.

in collaboration with
Dartmouth-Hitchcock Medical Center

The opinions expressed in the journal, Lahey Clinic Medical Ethics,
belong to the individual contributors and do not represent the institutional position
of Lahey Clinic on any subject matters discussed.