Clinical equipoise

A randomised trial is only ethical if there is genuine uncertainty in the expert community about which arm is better. That state is called clinical equipoise. It does not require every doctor to be undecided; it requires that reasonable, informed clinicians disagree, or that the evidence is too thin for anyone to be sure. Once a trial has settled the question, equipoise is gone and it becomes unethical to keep randomising, which is why data monitoring committees can stop a trial early for benefit or harm and why a trial answering a question that has already been answered elsewhere should not be run.

Equipoise explains several features of cancer trials that patients find puzzling. Placebo is only ever added on top of the standard treatment, never given instead of it, because withholding effective care would break equipoise. Trials of an approved drug against an older standard often allow crossover at progression, so no one is denied a treatment known to work. And when a single-arm trial shows a very large effect in a disease with no options, regulators may accept it without a randomised trial because randomising patients to the alternative would be hard to justify, as with larotrectinib in NAVIGATE or eflornithine in NMTRC003.

Equipoise can be violated in both directions. ProtecT randomised 1,643 men with screen-detected prostate cancer to active monitoring, surgery or radiotherapy at a time when many surgeons thought monitoring was obviously inferior; fifteen years later prostate-cancer mortality was low and not significantly different, so the doubters were wrong and the trial was right to run. MARS 2 randomised patients to a major mesothelioma operation that many surgeons believed in; survival was worse with surgery, which is exactly why a belief is not evidence. The therapeutic misconception is the patient's side of the same problem: joining a trial in the belief that the experimental arm must be better, when the whole point is that nobody knows.