New Methods of Conducting and Evaluating Clinical Trails

One particular initiative designed to evaluate psychiatric medicines is the New Clinical Drug Evaluation Unit Program (NCDEU) funded by the NIMH, which comprises over 1000 clinicians and industry and regulatory personnel. The NCDEU recently addressed the question of whether clinical trials of antidepressants reflect drug potential, and several groups involved in the initiative focused on different aspects of trial design, e.g., heightened placebo effect from such factors as a high dropout rate, poor site selection or poor protocol design, and their effect on masking the potential of active drugs. The NCDEU team reviewed 37 clinical trials, all of which had used the HAM-D. The HAM-D 'depressed mood' items according to DSM-IV-TR/ICD-10ACC are defined by the following core criteria37:

• persistent anxious or 'empty' mood;

• feelings of hopelessness, pessimism;

• feelings of guilt, worthlessness, helplessness;

• loss of interest or pleasure in hobbies and activities that were once enjoyed, including sex;

• decreased energy, fatigue, being 'slowed down;'

• difficulty concentrating, remembering, making decisions;

insomnia, early morning awakening, or oversleeping; and

• appetite and/or weight loss or overeating and weight gain.

Also included in this evaluation were the CGS-I severity and CGS-I improvement scores to measure improvement from baseline at the end of week 6 and week 8 of the acute NCE treatment phase. In 13 (35%) of the trials, efficacy was not demonstrated on any of the four measures, and certain SSRIs achieved only 50% at best. The importance of controlling the confounding variables in the development of a new antidepressant compound is clear from the NCDEU findings.37 In another study, the NCDEU team found that spontaneous improvements of depressive symptoms contribute to the placebo effect. Retrospective analysis showed that in placebo-controlled depression trials, the placebo effect is more prominent during the single-blind placebo run-in phase. The difference was unlikely to be due to different rates of spontaneously improved depression between the two trial phases. In addition to validating an NCE, comparisons were made between fixed-dose clinical studies to establish a minimal effective dose of the new agent and discourage subsequent use of excessively high doses with associated heightened side effects. It is argued that variable dose studies are more cost effective when attempting to demonstrate efficacy, whereas fixed-dose studies require larger sample size and subject the patients to either too low or too high a dose of a novel drug.

Another variable that demands attention is the adequacy of the statistical methods used to account for subject dropouts in clinical studies. Some forms of statistical analysis can make untenable assumptions, which are confounded by trial design. The introduction of computerized survival analysis at any single time point helps to distinguish between patients who remit at different times during a trial and those who remit by a particular time point. Survival analysis is now being used as a research tool that enables the statistical power of a study to be planned with more precision and the size of the treatment effect to be determined more accurately.34

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