Tragedy and the Clinical Trial: Part 2

On October 1, I wrote about the New York Times Story about two cousins in the US, Brandon and Thomas, both with a lethal form of melanoma, who were also both enrolled into a Phase III Clinical Trial to test a new, breakthrough cancer drug. One cousin got the wonder drug, PLX4032, while the other cousin got what the author claims that oncologists consider to be the significantly inferior “standard of care” drug dacarbazine (alongside a plaintive apology from his treating physician). Here’s a link to the original blog entry: A Tale of Two Cousins: Tragedy and the Clinical Trial

As I noted in the original blog entry, there are a number of very serious questions and issues raised by this story. The first is about clinical equipoise. What’s clinical equipoise? Well, here’s an “Equipoise 101” version. We think of clinical equipoise as genuine uncertainty over whether a treatment will be beneficial. In clinical trials, where researchers are comparing one treatment to another, it refers to the uncertainty over what the preferred treatment might be. Most of the time, researchers and clinicians have a suspicion or a hypothesis that one treatment may be superior to another in, for example, treating a particular condition or illness. Until adequate evidence exists in favor of one treatment over another, the hypothesis remains unproven and some degree of clinical equipoise still exists. Once sufficient evidence favoring one treatment over another exists, researchers have an ethical obligation to end a trial as equipoise no longer exists.

The current treatment that is provided and recommended for patients is known as the “standard of care”. In this case, it’s clear that clinical equipoise no longer exists, if it ever did. The standard of care in this case is dacarbazine, a drug that, according to the story, no oncologist wants to give. It’s ineffective at both shrinking tumours in a significant way and prolonging life. So to compare (by experimental use in seriously ill patients) a clearly inferior agent to what has been proven to be a markedly better drug seems, at first glance, unethical.

The structured phases of clinical trials, in some ways and in some cases, are antithetical to the notion of clinical equipoise as a measure of collective doubt at a particular point in time. Rigour demands that we strictly follow the phases of clinical trials to, in part, protect the best interests of patients. Yet, in the case of PLX4032, it’s difficult to see that the best interests of anyone are actually being protected. With a standard drug that is felt to do more harm than good, and an experimental “wonder” drug that has, in early phases of testing, produced dramatic responses but caused few serious side effects, this might seem like a case in which the highly-structured and years-long process of conducting clinical trials might be re-evaluated. Many might understandably object, saying that the clinical trial structure ensures that by the time a drug is actually available on the market, it has been through enough experimentation that physicians can be confident in prescribing it without worrying about unexpected harms to individual patients. True. But it’s not surprising that, in the case of what is seemingly a “wonder” drug for seriously ill patients with few to no other options, many oncologists in this story wondered if it’s time to reexamine whether the demands of rigour or the demands of ethics really require continuation of a two-armed trial.

It’s certainly something to think about. It seems to me that once the physicians involved in a trial are apologizing to a participant for being enrolled in a particular arm of a trial, we are no longer in a state of clinical equipoise.

~ by Nancy Walton on November 21, 2010.

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