A PROSPECTIVE, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, CLINICAL TRIAL COMPARING ...

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By Frederick "Yaybob" Ziffel (about the author) Page 1 of 2 page(s)

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You've probably heard a phrase like this one and wondered precisely what the words meant. Lets take a few minutes to discuss these terms, what they mean, and why they are preferred features of a study.

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These words describe the way a medical study is designed and implemented. Some group of investigators somewhere wants to answer some scientific question and they do and they review experimental data. The value of the results of the study is greatest if the study is as described in the title of this piece: prospective, not retrospective; double-blinded, not single-blinded or unblinded; etc.

Prospective. This word, which literally means looking forward, means that the data that was analyzed in the study was collected for that study. It is also possible to study old data from experiments already done for other purposes, a so-called retrospective (looking back) study. But thus is a flawed methodology and can produce erroneous conclusions.

A famous illustration of that surfaced recently and caused an abrupt reversal of the position of the American College of Obstetrics and Gynecology on the use of estrogens in postmenopausal women. These are women who are no longer ovulating either due to natural menopause or due to surgical menopause, usually as part of a hysterectomy.

The older, retrospective data suggested that estrogens were cardioprotective or heart healthy - in these women. It was noticed that there was a positive correlation between postmenopausal estrogen usage and a lowered risk of heart attack. That is, women who were taking supplemental estrogen died older and had fewer heat problems along the way than the postmenopausal women who didn't receive it. This, of course, suggested that all menopausal women benefit from and should receive supplemental estrogen.

But that conclusion was gleaned from old, retrospectively studies data originally collected for another purpose. Eventually, decades later, a prospective study using new data from new patients studied specifically for that purpose was performed. It showed that women started on supplemental estrogens two or more years after menopause actually had *more* heart disease and died younger because of it, the exact opposite of the retrospective study's conclusion. Take a moment if you like, to think about how this could be - why the data might tell us that estrogens help the hearts of postmenopausal women if examined retrospectively, but tell us the opposite when a prospective analysis is performed.

The answer is that the women that were receiving estrogen were also receiving other regular medical care, and they lived longer for that reason. The untreated postmenopausal group was mostly women who didn't see doctors regularly. They would have been treated with estrogen if they had been seeing doctors since that was the standard of care at that time. This also suggested that they were better off financially to afford more health care, and probably better educated if financially more secure.

All of these differences improved their life expectancy, not the estrogens. The estrogens actually caused a partial loss of the gains of education, money and regular medical care. But not enough to offset those advantages, so they did better *despite* the estrogens. The two groups being compared were different in more ways than just the one of interest: estrogen use or not. The estrogen takers were also healthier (and wealthier and smarter) to start with, and that, not the estrogens, was their advantage.

Bottom line: if the study is not prospective, beware.

Randomized. In a nutshell, this means that there is a control group of identical patients that does not receive the treatment of interest. The control group is like the study group in every other measurable way that might be relevant, such as average age, coexisting diagnoses, average weight, fraction that smoke, etc.

The study discussed above failed to meet this criterion since the control group (nonestrogen users), as already stated, was different from the study group (estrogen takers) not just in the way of interest, but also in mean income and frequency of doctor visits.

When the estrogen study was repeated using prospective data, the patients were randomized into two identical groups. One group got treatment, the other did not. In all other ways, they were identical. Now, only a very unlikely statistical fluke could produce a wrong conclusion.

Placebo controlled. This means that control group, or the untreated group, received a sham treatment - or placebo - so that they could not tell that they were receiving no treatment. This allows us to keep the patients in the dark, or "blinded". If they knew, it might affect their responses.

The science of placebos can be quite challenging when the treatment being studied is bypass surgery and you awaken from "surgery" with no chest scar. Or perhaps we're studying the effects of pregnancy history on breast cancer. Pregnancies are thought to reduce its risk. But it's pretty hard to have a study group with kids and a control group with none with neither knowing if they have kids or not. The importance of that will be seen next.

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