10/08/2010 08:34 am ET | Updated Nov 17, 2011

The Problem With Randomized Clinical Trials for Medical Research

Writing in the New York Times on Sunday, September 19, Amy Harmon chronicles one of the most painful downsides of contemporary medical research. She tells the story of two cousins--Thomas and Brandon--both of whom were diagnosed with terminal cases of melanoma (skin cancer). In this era of what we call the new grief, in which whole families get swept up in a prolonged crisis that begins with a terminal diagnosis, their story takes a dark turn that, were it not for efforts such as Harmon's, would not see the light of day that it badly needs.

As it turned out both Thomas's and Brandon's cancers were characterized by a type of tumor that had been found, in preliminary research, to respond to a new drug that was being tested in what is commonly called a "randomized clinical trial." In this type of research, which is prevalent in the drug industry, a group of patients with a particular diagnosis (such as the form of melanoma that Thomas and Brandon had) is identified. Then, in order to test the effectiveness of the new drug, half of this group is designated to receive it, while the other half is given some other treatment. In this case, the "other" treatment was a drug that had pretty much been found to be ineffective in arresting this type of melanoma. The assignment to one group (the "treatment" group) or the other group (the "control" group) is completely random.

In this story, Thomas received the new drug, while Brandon, as luck would have it, was assigned to the control group, meaning he would receive infusions of a chemotherapy drug that had been "notoriously ineffective in treating melanoma for 30 years." When Brandon's distraught mother confronted the UCLA doctor heading the study about her son being relegated to a treatment that was widely believed to be ineffective, all the physician could say was "I'm sorry."

After being placed on the new, experimental drug, Thomas' tumors got smaller. He felt better--good enough, in fact, to get a job building fences on a ranch. Meanwhile Brandon, in his capacity as a "control" subject receiving "treatment as usual," could barely drag himself to work and spent most of his time sleeping. As for how he felt, Brandon would tell his mother, "You have no idea what this feels like. I just hurt."

Randomized clinical trials are not unique to medical research, though their dark side, as evidenced by the above story, may be most striking there. This methodology is used to test the effectiveness of other drugs (antidepressants, sleep aids, etc.) as well as other types of interventions (treatments for drug abuse, etc.). It has an eminently reasonable rationale: how can we know for sure if a treatment works unless we compare it to something else? And what better to compare a new treatment to than an old, established one?

If we are talking about a new treatment for substance abuse, or a new sleeping pill, the idea of conducting randomized trials may seem relatively benign. All things considered it would be hard to argue that the people who receive the "treatment as usual" for a substance abuse problem were being treated cruelly. When applied to treatments for terminal illnesses, on the other hand, the idea of randomized clinical trials can raise the hairs on the back of many people's necks, including mine. The kicker here--for me at least--has to do with how a drug is deemed to be effective (or more effective than "treatment as usual.") It appears that, as far as cancer treatment is concerned, the bottom line is how much longer patients receiving the new treatment live. In other words, if those in Thomas' group lived, on average, 12 months longer than those who were in Brandon's group, the new drug would be deemed to be "effective."

But is longevity necessarily the only (or even the best) way to evaluate effectiveness? What about side-effects? What about quality of life? Many cancer drugs have pernicious side-effects. Jackie Kennedy is only one example of someone who decided to discontinue cancer treatments because of their side-effects. Other drugs, though they might not stave off death for very long, can make a big difference in a patient's daily life. In the study that Brandon and Thomas were part of, for example, the fact that the new, experimental drug dramatically shrunk tumors, many of which could lead to intense pain, made Thomas' life significantly better. Is this not a meaningful measure of "effectiveness?"

Many oncologists, reacting to this dark side of clinical trials (and with empathy for their patients and their families) have begun to lobby for alternative ways to assess effectiveness. They have also begun to lobby for expanding what is known as "compassionate use" of promising experimental treatments for patients who are suffering, who have not responded to other treatments, and who would have qualified for the new drug were it not for their random assignment to a control group.

The ways in which modern medical technology has successfully arrested or cured previously terminal illnesses, as well as how it has successfully prolonged life in the terminally ill, has also had unintentional consequences. Chief among these is the prolonged process that not only the terminally ill patient, but the entire family, must endure. My colleague Dr. Barbara Okun and I are advocates for finding ways and resources to help families navigate these difficult waters. We can only imagine what Brandon's mother and family--not to mention Brandon himself--must have endured.

Readers of this blog who wish to support those who would advocate for a broader definition of--along with the pursuit of more humane methods for measuring--treatment effectiveness would do well to make their opinion known, to federal agencies, to legislators and to advocacy groups such as The American Cancer Society.