The patients who volunteer for a randomized trial are sacrificing a great deal of autonomy. They giving up the right to determine which drug they get and they are ceding this authority not to an expert but to a random device. You should not abuse that gift by asking them to participate in a trial where they have a 50% chance of getting a treatment that is known to be inferior. This is especially difficult when one of the choices is a placebo. There is a hot debate about when a placebo arm is ethically acceptable.
This debate is the sharpest when researchers have used a placebo surgery to maintain blinding. In general, it is difficult to blind a surgical trial. If one of the arms of your research study involves a bilateral orchiectomy, sooner or later your patients are going to notice that something is missing.
Sometimes you can blind the comparison between a small incision and large incision by placing a large bandage on every patient and staining the bandage with iodine to hide the lesser blood loss with the small incision.
- A. G. Johnson, J. M. Dixon. Removing bias in surgical trials. British Medical Journal 1997: 314(7085); 916-7. Article is behind a pay wall.
But perhaps the greatest effort to keep a surgical procedure blinded occurred in a study of fetal cell implants as a treatment for patients with Parkinson’s disease. In that study, patients in the control group underwent a surgery where holes were drilled in the skull, but no fetal cells were inserted. There was a fury of criticisms of this trial. My favorite critique has a wonderful title.
- C Weijer. J Law. I need a placebo like I need a hole in the head. Med Ethics 2002: 30(1); 69-72. Article is behind a pay wall.
Dr. Weijer notes that this intervention required the control patients to undergo the following:
- placement of stereotactic equipment
- scalp incisions
- partial burr holes,
- general anesthesia,
- intravenous antibiotics, and
- low-dose cyclosporin.
I’m not a doctor, but I suspect that each of these steps carries a non-trivial risk of harm. Can we ethically ask patients to suffer the risk of harm in order to provide information with a greater degree of scientific credibility? The answer is yes is some circumstances, but you have to proceed cautiously. We live in a society where a few individuals are allowed to donate a kidney to a total stranger. If someone asks to do this, of course, you have to proceed cautiously and make them understand what the risks of the surgery are and what the risks are of living the rest of your life with only one kidney.
But there’s an equally important consideration. Patients will not volunteer for a study where one or more of the options are perceived by them to be inferior. In the era before AZT became available (prior to 1987), AIDS was considered a death sentence. So when researchers wanted to try to test new therapies, and insisted on a placebo arm, the patients rebelled. They tried to subvert the intent of the trials by doing one of two things. Some patients would get together in small groups and would pool their medication. They would grind up all the pills and then redistribute them. They felt that a half dose of a promising new drug would be a better choice than a 50% chance of getting an ineffective placebo. Other patients would take their first batch of pills to a chemist for analysis. If they found out that they were taking sugar pills, they would drop out and re-enroll under a different name.
You can’t blame the patients for this behavior. They are acting in their best interests. In fact, it was largely because of the AIDS crisis that researchers have recognized that the placebo controlled trial is not an absolute requirement in all research studies. There is now general consensus that in a disease that has close to 100% morbidity or mortality, there is no need for a control group at all. Any treatment that is helps even a small fraction of patients to survive will stand out clearly against a background rate of 0% survival.
You can find an earlier version of this page on my old website.