Maintaining Balance

We all struggle with balance. Splurge today vs. save for tomorrow, enjoyment vs. discipline, rest vs. exercise, career advancement vs. life enhancement…an endless series of choices that define our lives. For those of us in the pharmaceutical industry, there is another kind of balance: the objective, unbiased outlook of the ideal clinical investigator. We even have a name for this special kind of balance: equipoise.

The term “equipoise” is derived from the Latin word aequus, which means level or even, and the Middle English term “pois,” which literally means weight. Together, equipoise could refer to an even or equal distribution of weight or emphasis…and that is exactly how most dictionaries define it.

Clinical equipoise describes a position of scientific indifference between two competing therapeutic regimens. An investigator who presumes that the test article will perform better or worse than the control article should be excused from the study. Investigators and dispensers often are ‘blinded” to prevent this type of bias.

But what about a placebo-controlled trial? Can an investigator be truly impartial when they know that some percentage of their study participants will receive the veterinary equivalent of a sugar pill? A related question: Isn’t an investigator morally obligated to offer patients the best known therapy to treat a condition?

My experience on the human side was eye-opening. In many instances, study investigators were encouraged to participate in placebo-controlled trials to avoid compromising the scientific merit of study with a positive control, provided that the patient would benefit and suffer no or little harm. When I offered a similar scenario to 34 private-practice veterinarians, several expressed strong reservations. One veterinarian explained his reluctance by saying, “I would have serious ethical issues administering what could be a placebo to an animal with a known problem, since they are not able to consent to their study participation as a human could.” But some suggested that, under certain circumstances, they might participate in a placebo-controlled trial. For example, if they felt that the known and proven treatment were not the best treatment for their patient, then they would be morally and ethically comfortable enrolling that patient in a placebo-controlled trial and able to maintain an impartial perspective throughout the study.

Let’s say that a new anti-infective compound is being evaluated in a placebo-controlled trial with rescue after 24 hours. Safety and efficacy have been proven, and dose ranges have been established. How challenging do you think it would be to recruit veterinarians to serve as investigators? And could they maintain clinical equipoise throughout the study? Not too long ago, I posed that situation to 45 veterinarians, 34 in private practice and 11 at academic hospitals. All but one of the private-practice veterinarians was not willing to be an investigator, citing ethics and a moral obligation to provide some kind of treatment for an infection. The remaining private-practitioner felt that he might participate provided that the anticipated risk was well known and that the animal would suffer no significant harm if assigned to the placebo. The academic veterinarians were unanimous in their desire to first know how much pain or damage the placebo group would sustain, whether the damage could be life-threatening, and at what point rescue medication would be introduced. What was very clear was that all of the veterinarians were more concerned with the design of the study and its effect on the study subjects than on their ability to maintain an impartial outlook.

To get a pet owner perspective, I conducted a very unscientific survey of 27 dog owners whom I encountered while walking along a river-side path during a recent vacation. I asked each owner, “If your dog had a serious condition that none of the available treatments had been able to remedy, would you enroll them in a placebo-controlled trial, knowing that there was a chance they would receive the placebo?” All 27 said that they would. None cared much about the design of the study or whether the investigator would remain impartial during the trial. Their main focus was the possibility of a cure for their pet. And when I probed on that, they all gave me some variation of “because they’re a member of the family!” How’s that for balance?