The trial design we will be most concerned with here is that of the long-term controlled randomized clinical trial. By controlled
13See, for example, Moore et al. (1998) and Chapter 8 of Good (2001).
randomized clinical trial we mean a comparison of at least two treatment regimens one of which is termed a control.
Generally, though not always, as many patients will be assigned at random to the control regimen as are assigned to the experimental one. This sounds expensive and is. You're guaranteed to double your costs because you have to examine twice as many patients as you would if you tested the experimental regimen alone. The use of controls also may sound unnecessary. Your intervention works, doesn't it!
But the foreseen happens. You get the flu. You get a headache or the runs. You have a series of colds that blend one into the other until you can't remember the last time you were well. So you blame your silicon implants. Or you resolve to stop eating so much sugar. Or, if you're part of a clinical trial, you stop taking the drug.
It's then that as the sponsor of the trials you're grateful you included controls. Because when you examine the data you learn that as many of the control patients came down with the flu as those who were on the active drug. And those women without implants had exactly the same incidence of colds and headaches as those who had them.
Two types of controls exist: passive (negative) and active (positive):
A negative control or placebo in a drug trial may consist of innocuous filler, though the preparation itself should be matched in size, color, texture, and taste to that of the active preparation. A negative control would be your only option with disease conditions for which there is no existing "cure."
More often, there exists some standard remedy, such as aspirin for use as an anti-inflammatory, or metoprolol for use in alleviating hypertension. In such cases you would want to demonstrate that your preparation or device is equivalent or superior to the existing standard by administering this active preparation to the patients in your control group. Barbui et al. (2000) and Djulbegovic et al. (2000) recommend that an active control always be employed. Barbui et al. (2000) insist that to protect the patient, only an active control should be employed. Depending on your requirements and those of the regulatory agencies, one or both types of control may be needed.
Let's reflect on the consequences of not using controls. Who knows (or will admit) what executive or executive committee at Dow Corning first decided it wasn't necessary to do experimental studies on silicon implants because such studies weren't mandated by government regulations? It's terrifying to realize the first epidemio-logical study of whether breast implants actually increase the risk of certain diseases and symptoms wasn't submitted for publication until 1994, whereas the first modern implants (Dow Corning's Silastic mammary prosthesis) were placed in 1962.14
It's terrifying because the first successful lawsuit in 1984 resulted in a jury award of $2 million! Award after award followed with the largest ever, more than $7 million, going to a woman whose symptoms had begun even before she received the implants.15 Today, the data from the controlled randomized trials are finally in. The verdict—silicon implants have no adverse effects on the recipient. Now, tell this to the stockholders of the bankrupt Dow Corning.
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