Controversy regarding potential treatments and vaccines for COVID-19 has brought arguments about randomized trial methods into the public square. Disagreements about interim analyses and early stopping of vaccine trials have moved from the methods sections of medical journals to the editorial section of the Wall Street Journal. I never imagined a rowdy public debate about the more sensitive Pocock stopping rule versus the more patient O’Brien-Fleming rule. A randomized trial nerd like me should be heartened that anyone even cares about the difference. I imagine it’s how Canadians feel during Winter Olympic years when the rest of the world actually watches curling. But the debates have grown so heated that choice of a statistical stopping rule has become a test of political allegiance. And that drove me to some historical reading about the concept of equipoise.
As originally understood, the ethical requirement for equipoise in randomized trials applied to the individual clinician and the individual patient. Each clinician was expected to place their duty to an individual patient over any regard for public health or scientific knowledge. By that understanding, a clinician would only recommend or participate in a randomized trial if they had absolutely no preference. If they preferred one of the treatments being compared, they were obligated to recommend that treatment and recommend against joining a randomized trial.
In 1987, Benjamin Freedman suggested an alternative concept of “clinical equipoise”, applied at the community level rather than to the individual patient. A clinician might have a general preference for one treatment over another. Or the clinician might believe that one treatment would be preferred for a specific patient. But that clinician might still suggest that their patient participate in a randomized trial if the overall clinical or scientific community was uncertain about the best choice.
Freedman’s discussion of equipoise offers some useful words for navigating current controversies regarding COVID-19 clinical trials. He suggested that a clinician could ethically particicipate in a randomized trial or recommend participation to their patients “if their less-favored treatment is preferred by colleagues whom they consider to be responsible and competent.” A clinician is not expected to be ignorant or indifferent (“I have no idea what’s best for you.”). Instead, they are expected to be honest regarding uncertainty (“I believe A is probably better, but many experts I respect believe that B is best.”). Freedman proposed that a randomized trial evaluating some new treatment is ethically appropriate if success of that treatment “appears to be a reasonable gamble.” That language accurately communicates both the hope and uncertainty central to randomized trials of new treatments. It also communicates that odds of success can change with time. A gamble that appeared reasonable when a randomized trial started may become less reasonable as new evidence – from within the trial or outside of it – accumulates. Reasonable investigators must periodically reconsider their assessments of whether the original gamble remains reasonable. That’s where those stopping rules come in. The concept of clinical equipoise also helps to frame our MHRN randomized trials of new mental health services or programs. We are often studying treatments or programs that we have developed or adapted, so we are neither ignorant nor indifferent. We certainly care about the trial outcome, and we usually hope the new treatment we are testing will be found helpful. But we do randomized trials because our beliefs and hopes are not evidence.
Greg Simon
That last sentence is real important. Thanks Greg.