imported_womens-health

Cracking the Clinical Trials Code

By: Frederick Munschauer III, MD
By: Jeffrey Greenstein, MD
New treatments for disease are constantly being tested in clinical trials, and a lot of patients pay close attention to their results, hoping to learn about the latest medication that will change their lives. But the data from these trials is easy to misinterpret, and it can lead to unnecessary fears or false hopes. Below, clinical trial experts Drs. Jeffrey Greenstein and Frederick Munschauer discuss how patients can best evaluate clinical trials, and steer clear of disappointment and confusion.
Q: What is a clinical trial?
DR. FREDERICK MUNSCHAUER: A clinical trial is a very well-designed experiment whose purpose is to test the safety and efficacy of a drug. This is done by selecting patients who are relatively similar, and randomly assigning some to the drug being tested and some to a placebo (sugar pill containing no medication). The group is followed over a period of months or years, to see whether the group of patients taking the drug does better than the patients taking the placebo. If the patients on the drug do better, we must evaluate whether the rate at which they are improving compared to the placebo group is statistically significant, or if it is just chance. That's a clinical trial. It represents a major achievement of medicine, and it's the only way to really evaluate both the safety and efficacy of a drug.

Q: Could you describe the different phases of a clinical trial?
DR. JEFFREY GREENSTEIN: There are actually four phases of a clinical trial. The first phase tests the drug in people who are healthy, to see whether or not there are adverse side effects. In phase II, we begin to use the drug in a person with a disease that we hope to treat. In phase II, we're primarily interested in whether or not the drug is safe to use, but we're also hoping to glean some information as to whether or not there may be potential efficacy. However, we can't prove efficacy in this phase because it's usually too small a study to give us what we call "statistical power."

Then we move on to the phase III study, which is really the gold standard of proving whether or not a drug actually works. These are the kinds of studies that determine whether or not a drug is truly effective, and have been done in the drugs, for example, that are marketed and FDA-approved for the use of treatment in MS.


Finally, we go on to phase IV studies. These are so-called "post-marketing studies." The drug is, by this time, approved by the FDA, and now we're concerned about it's long-term safety. A phase III study may run for two or three years, but a phase IV study can go much longer. During phase IV, we're looking for long-term effects of the drug, including any adverse effects that weren't discovered in earlier phases.

Q: How do you establish dosage for a clinical trial?
DR. JEFFREY GREENSTEIN: Dosage is usually established in the phase I and the phase II studies. We look for a dosage that is both effective and safe. We do this by initially testing a range of doses, some too low to be effective, and some that are as high as can be tolerated, and some in between. Then we select a dose based on these tests.
Q: How does a patient evaluate a clinical study when they hear about it in the news or from their doctor?
DR. FREDERICK MUNSCHAUER: It's very difficult for patients. Even physicians sometimes have difficulty evaluating a phase III clinical trial. If you hear about a trial in the media, try to determine whether it is a new agent being tried on mice or whether it's an agent being studied on a large number of individuals with the disease. That's the first question. What people are looking for is a double-blinded, placebo controlled, prospective trial. Those are words to look for.

"Double-blind" means that neither the patient nor the physician taking care of the patient, know whether the agent that's being administered to the patient is the real drug or a placebo. A placebo is like a sugar pill. It is a medication that has no known effect, but no toxicity, either. So that's what we refer to as a placebo control.

"Prospective" means that you identify a group of patients and you start them on one of these two treatments, the placebo or active drug, and you follow them over time and watch to see whether or not the agent that you feel is the active agent, the real drug, has a beneficial effect in treating the disease.


Q: What about the size of the trial? If you have a drug, and one person gets better normally, and then after taking the drug, two people get better, it's 100 percent improvement, but does that really count with such a small sample size?
DR. JEFFREY GREENSTEIN: No. In going to phase III studies, we try to define how large a difference we might be able to measure. For the most part we look at things like a 30 percent or a 50 percent difference in outcome between the drug being studied and placebo, not 100 percent difference. The statisticians calculate the number of patients needed to show the difference, if in fact that difference actually occurred during the study. They also define a number of different statistical methods that tell us whether the results of the study have occurred by chance or really are reflective of true therapeutic benefit from a treatment that's been tried. You have to do better than chance.

Q: Are these clinical trials designed with pharmaceutical marketing objectives in mind?
DR. FREDERICK MUNSCHAUER: A lot of clinical trials are done on agents which have little or no commercial value. But, yes, the pharmaceutical companies design innovative drugs that they hope will treat a disease, and that they won't go broke making.

You do need to evaluate the process by which any drug is held to be an effective therapy. Testing a drug on twenty people is not science and should not be taken as science. That's very different from a study that's supported either by the pharmaceutical industry or the National Institute of Health, since these groups use the kinds of rigorous scientific methods we are outlining here.

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