Placebo, definition

When our most recent - and most definitive - meta-analysis was published, the headlines in many newspapers blazoned that antidepressants don t work .1 The Daily Telegraph headline phrased it more specifically, clarifying that antidepressants are no better than dummy pills ,2 but even this headline was not entirely accurate. What our analyses actually showed was that antidepressants work statistically better than placebos, but that this statistical difference was not clinically meaningful. It was too small a difference to be of much importance in the life of a severely depressed person. 

The question whether lutein and zeaxanthin can contribute to lowering the risk for AMD cannot be answered unequivocally by epidemiological studies. Only randomized controlled trials (RCTs) during the course of which xanthophylls are supplemented in a double-blind, placebo-controlled, and randomized manner, and in which results are evaluated according to clear predefined efficacy criteria (Seddon and Hennekens 1994) have the potential to provide definitive answers. The specific long-term time-course and intricate nature of AMD make the design of such studies difficult, however. 

No definitive conclusions can be drawn concerning a possible role of rifaximin in preventing major complications of diverticular disease. Double-blind placebo-controlled trials with an adequate sample size are needed. However, such trials are difficult to perform considering the requirement of a large number of patients. Assuming a baseline risk of complications of diverticular disease of 5% per year [2], a randomized controlled trial able to detect a 50% risk reduction in complications should include 1,600 patients per treatment group considering a power of 80% (1 - (3) and an a error of 5%. 

Since a high spontaneous cure rate has often been observed [40], double-blind, placebo-controlled trials are needed to definitely assess the efficacy of rifaximin in the treatment of BV. 

Erlotinib (Tarceva) took a differenf approach to a pivotal trial. In the study of Tarceva for patients with advanced, previously treated non-small cell lung cancer, where survival was the primary endpoint, patients were randomized to receive either Tarceva or placebo. Tarceva clearly prolonged overall survival (6.7 vs. 4-7 months, p = 0.001). In addition, Tarceva improved progression-free survival, and improved fime-fo-deferiora-tion of patients reported symptoms (cough, dyspnea, and pain). Obviously, this was a definitive trial (drug vs. placebo) however, it could be a controversial trial as it was a survival trial with no provisions to crossover to the active Tarceva. It is doubtful fhaf many trials with this noncrossover design (with a survival endpoint) will be done in the future. 

Results from two large multicenter trials evaluating SRIs for the treatment of dysthymia were similar to those found above (M. Steiner, personal communication, December 1995 Halbreich et ah, in press). In a study evaluating the efficacy of sertraline versus that of IMl and placebo for the treatment of dysthymia, women were again found more likely to respond to sertraline than to either IMI or placebo. Similarly, dysthymic women treated with paroxetine were more likely to respond using a definition of 50% decrease in the HRS-D. In this latter case, 54% of women treated with paroxetine responded compared with 21% of women treated with placebo, whereas 30% of men in either treatment cell responded (M. Steiner, personal communication, December 1995). 

The optimal duration of treatment with cholinesterase inhibitors has not been definitively established. Most randomized controlled trials in patients with mild to moderate Alzheimer s disease have been 26 weeks in duration or less. However, some data (mostly open-label continuation data of placebo-controlled trials) suggest continued benefits with treatment for 1 year or longer (Bullock and Dengiz 2005 Doody et al. 2001a Farlow et al. 2000 Grossberg et al. 2004 Lyketsos et al. 2004 Mohs et al. 2001 Pirttila et al. 2004 Raskind et al. 2000, 2004 Rogers et al. 2000 Small et al. 2005 Wilcock et al. 2003 Winblad et al. 2001). 

Phase III studies represent the confirmatory phase of drug development, which takes several years and usually involves several thousand patients at multiple trial centers. Large patient numbers are required in these trials to provide convincing documentation of clinical efficacy and safety, a more complete adverse event profile and covariates and estimates of variability in dose response relationship due to individual differences in pharmacokinetics and pharmacodynamics. They are aimed at definitively determining a drug s effectiveness and side-effect profile. Most of these studies are double-blind and placebo-controlled, sometimes with the option of open-label long-term extensions. 

The risk of relapse in discontinuation trials depends on many non-pharmacological, often poorly controllable factors, notably the expectations of the patients, doctors and nurses, other environmental factors, the duration of hospitalization and prior treatment, and the time interval since the last acute psychotic episode. On the basis of an analysis of 14 discontinuation trials, Kane and Lieberman (1987) found that the relapse rate varied greatly from study to study depending on the trial, relapse rates of 30 86% with clustering around 60 70% have been reported in the first 12 months after placebo substitution. According to Kane and Lieberman, this scatter is a result of the different inclusion criteria applied and the different definitions of relapse . 

Equally critical to a properly designed study is sample adequacy (i.e., size and appropriateness). It is hard to make definitive conclusions with very small sample sizes (e.g., five per group) because variation is too great. The minimal sample size needed to make inferences also depends on how large the experimental drug-placebo effect size is (i.e., the larger the effect size, the smaller the sample needed). 

HMG CoA reductase inhibitors can be associated with small rises in alanine transaminase activity, but have not been definitely associated with severe morbidity involving altered hepatic function. The results of randomized trials do not suggest that statins in standard doses are hepato-toxic. In none of the large randomized studies in which standard doses were assessed (atorvastatin 10 mg/day, fluvastatin 40-80 mg/day, pravastatin 40 mg/day, simvastatin 20-40 mg/day) was there any clear excess risk of hepatitis or any other serious liver-related adverse events. Long-term large randomized trials have confirmed an excess of persistent rises in transaminases with atorvastatin 80 mg/day compared with lower doses or placebo, and similarly some excess with simvastatin 80 mg/day, but hepatitis and liver failure were not reported (4). 

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