Clinical trial methodology and drug-placebo differences

As Khan and Brown (1) correctly note, the magnitude of the placebo response in antidepressant trials has increased over the years. But it is not only the placebo response that has increased. So too has the response to antidepressants, a fact that has been widely ignored. In the Walsh et al meta-analysis (2), the correlation between the placebo response and year of publication was r = .45; that between the response to selective serotonin reuptake inhibitors (SSRIs) and year of publication was r = .47, and the difference between the two remained relatively constant.

What might account for the finding that the response to both placebo and antidepressants has increased over the years? One thing that it points to is that the drug effect and the placebo effect are probably additive. That is, the response to antidepressants comprises the effect of the drug and the response to placebo, so that when the placebo effect increases, so too does the response to the drug (3). What, then, is responsible for the increase in antidepressant and placebo responses over the years? It cannot be due to decreased baseline severity in more recent trials, because pharmaceutical companies abandoned including mildly and moderately depressed patients in efficacy trials after finding that these patients did not benefit beyond placebo (4). A more likely explanation is that marketing has led to increased public perception that antidepressants are effective, thus enhancing the placebo effect, and because the placebo effect is a component of the drug response, the latter also increased.

As Khan and Brown note, “if you lower the risk of exposure to placebo, then the apparent therapeutic effect with the antidepressants and placebo is greater”. Once again, these data suggest additivity. Increasing expectancy of getting a drug rather than a placebo increases the response to the drug and the placebo (5–7).

According to Khan and Brown, the last observation carried forward (LOCF) method acts to minimize antidepressant-placebo differences. My colleagues and I made the same assumption when conducting our first meta-analysis of the trial data submitted to the U.S. Food and Drug Administration (FDA) (8). However, the data proved us wrong. LOCF analyses indicated greater drug-placebo differences than did the observed cases method, in which dropouts were excluded from the analyses.

Caution is needed when drawing conclusions from data indicating that higher baseline scores are associated with greater improvement in both drug and placebo arms. This is exactly what would be expected based on the statistical artifact of regression toward the mean. It is a very substantial effect that is often ignored. Elsewhere I have shown that when difference scores between two random variables are correlated with the score on one of them, the resulting correlation is about r =. 70 (9). This is the chance standard against which one might judge an association between baseline severity and improvement scores.

Finally, a note on the “quick and easy approval” of vilazodone by the FDA is needed. Trovis Pharmaceuticals submitted seven clinical trials to the FDA. The first five showed negative results. However, in one of these, the company noted a non-significant trend toward superiority of vilazodone over placebo on the Montgomery-Asberg Depression Rating Scale (MADRS), but not on the Hamilton Rating Scale for Depression (HAM-D), which had been used in previous antidepressant approvals as the primary outcome for assessing efficacy. Trovis Pharmaceuticals was then allowed to designate the MADRS instead of the HAM-D as the primary outcome measure for what were subsequently considered the two pivotal trials. The difference between vilazodone and placebo on the HAM-D improvement was only 1.69 points on the two “pivotal” trials and, considering all seven trials, it was only 1.01. The FDA approved labeling states that “the efficacy of VIIBRYD was established in two 8-week, randomized, double-blind, placebo-controlled trials”, but makes no mention of the five negative trials. In an internal memo dated May 4, 1998, P. Leber, writing in his capacity as Director of the FDA Division of Neuropharmacological Drug Products, stated his opinion that “labeling that selectively describes positive studies and excludes mention of negative ones can be viewed as being potentially ‘false and misleading’” (10), p. 11).

Despite these minor qualifications, the points made by Khan and Brown are well taken. Drug-placebo differences are small in efficacy trials, and most of the response to antidepressants seems due to expectancy.