AimsClinical trials constitute the gold standard to assess the efficacy and safety of new medicines. However, because they are conducted in standardized conditions far from the real world of prescription and use, discrepancies in patient selection or treatment conditions may alter both the effectiveness and risks. On the basis of three examples, our objectives were to study the differences between the characteristics of treated populations and treatment patterns in clinical trials and in postmarketing settings and to discuss the potential consequences on actual efficacy and safety. MethodsTreated populations were compared with patients included in premarketing clinical trials. Comparisons were made on the basis of demographic characteristics and treatment patterns. ResultsWhatever the indicator and the drug studied, differences were observed: from 0.04% to 63% for tacrine, from 0% to 37% for celecoxib and from 6% to 52% for simvastatin, with possible consequences on the effectiveness and safety of the drug concerned. Our results confirm the under-representation of women and elderly patients in premarketing clinical trials, e.g. an M : F ratio of 4.6 in clinical trails of simvastatin vs 1.0 in the joint population. Moreover, the concomitant use of medicines was made extremely restrictive by the protocols of these trials while this was not the case in the postmarketing phase. This has possible consequences on the effectiveness and safety of the drug concerned. ConclusionsThese results plead for systematic ad hoc observational postmarketing studies for any novel and/or expensive medicine to assess the relevance of premarketing data.

Although acetaminophen is a well established analgesic, its mechanism of action is still unknown. We investigated whether this drug could affect central monoaminergic neurotransmission in rats. Significant increases in serotonin (5-HT) levels were found in the posterior cortex, hypothalamus, striatum, hippocampus and brain stem, but not spinal cord, 45 min after per os administration of 200-400 mg/kg of acetaminophen. However, this treatment altered neither the levels of 5-hydroxyindoleacetic acid nor the accumulation of 5-hydroxytryptophan after blockade of aromatic L-amino acid decarboxylase. On the other hand, a decrease in both the levels of the dopamine (DA) metabolite, dihydroxyphenylacetic acid, and the accumulation of dihydroxyphenylalanine were noted in the striatum of acetaminophen-treated rats. Finally, acetaminophen administration significantly increased noradrenaline (NA) levels in the posterior cortex. In vitro studies showed that acetaminophen (1 mM) enhanced K+-evoked overflow of [3H]5-HT, but not [3H]DA and [3H]NA, previously taken up in brain slices, and exerted no direct effect on monoamine oxidase A, tyrosine hydroxylase and catechol-O-methyl-transferase activities. These results indicate that acetaminophen affects central monoaminergic neurotransmission, thereby suggesting that monoamines (especially 5-HT) might participate in its analgesic action.

Despite the ever larger choice of softwares and statistical packages allowing fast and accurate computation of binomial and Poisson confidence limits, there is always a need for a simple and reliable formula allowing non-computerized computations. The method proposed in this paper is derived from the Freeman and Tukey's variance stabilizing transformation for a random Poisson variable and adjusted for giving the best fit with the exact Poisson values. Despite its simplicity, allowing its use in any circumstances, this method provides very satisfactory results and a much better fit than classical formula based on the normal approximation, even if a continuity correction is used. It allows computation of Poisson confidence limits both for count or rates and proportions.