Evidence-based Medicine Analysis of Immunomodulatory Treatment for Multiple Sclerosis

Evidence-based Medicine Analysis of Immunomodulatory Treatment for Multiple Sclerosis

Morice Marie-Claude
Published: European Neurological Disease 2006 Issue 2
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Evidence-based Medicine and Trial Results

Evidence-based medicine (EBM) is the judicious and conscientious use of current best evidence in making decisions about the care of individual patients. It teaches physicians how to draw clinically
meaningful conclusions from clinical trials and how to compare results of different trials. In most trials, the active drug is compared with placebo and the results of different trials are not immediately comparable. EBM compares disease event (or bad outcome) rate. Disease event rate in the study population is compared with the expected disease event rate in the overall affected population, which is assumed to be similar to that of the group of patients treated with a placebo drug. The placebo reproduces all the psychological and even biological effects of taking a drug, being carefully followed up without taking the active drug.

Disease event rate is usually called the risk of the disease and the risk ratio (RR) is how many times the risk of the disease event is greater (or smaller) in the actively-treated group in comparison with the control or reference group. If the risk of the disease in the treated group is equal to the expected risk (the risk in the placebo group), this means that the drug was not effective and the RR is 1. If the disease risk was reduced by the active drug, the RR will be below 1, and to know if the reduction is significant the confidence interval (CI) is examined. CI is a measure of the uncertainty of study results, and is based on the idea that the same study, repeated on different samples, would not yield always the same result, but results spreading around the true unknown result. All these results are assumed to have a Gaussian distribution, and 95% CI includes most of the possible values of the Gaussian curve. If this range does not contain 1, this indicates that all risk ratios in this range have a less than 5% probability of being equal to 1; that is they are significantly different from 1 at a probability level below 0.05. This is usually assumed as a satisfactory level of significance. EBM also calculates the risk reduction that is to what extent the active drug reduces the probability of the disease event compared with the placebo group (always representing expected disease event rate in the population). The most informative figure is the absolute risk reduction (ARR). To be significant, ARR 95% CI should not include 0 (i.e. no risk reduction), nor any negative number (a negative risk eduction is a risk increase, i.e. in the group under study, disease event rate increased instead of decreased). Another informative figure is the number of patients needed to treat (NNT) to prevent the bad outcome of the disease event. NNT CI should not include 0 or a negative number or, on the other hand, infinity. If the NNT is 0 or a negative number, this means that you must not treat patients to prevent the bad outcome. If it is infinite, this means that you have to treat an infinite number of patients to prevent the bad outcome, i.e. you will never be able to prevent the bad outcome.

Finally, since all EBM measures are calculated from RR, the event rate should always be used in the control group as a reference. They are therefore normalised to the respective control group and can be compared from one trial to another.

The Major Clinical Trials in Relapsing-remitting Multiple Sclerosis

Interferon Beta

In 1993, the first randomised clinical trial (RCT) of interferon-beta (IFNβ) in relapsing-remitting multiple sclerosis (RRMS) was published. It included 372 patients randomised to receive placebo or IFNβ-1b for two years. IFNβ-1b at a dose of 250μg subcutaneously every other day, when compared with placebo, reduced the clinical relapse rate (-34%; p<0.0001) the primary end-point of the study. It also reduced the median number of T2 active lesions (-83%; p<0.009) and the median volume of T2 disease burden (-17.3%; p=0.001) on magnetic resonance imaging (MRI) scans. Risk ratios, absolute risk reductions and NNTs were all statistically significant for the primary clinical end-point (occurrence of relapses) and for MRI activity (see Table 1).

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