”6 The naturalistic approach represents essentially all types of observations which are not obtained in randomized clinical trials, but which are obtained during the activities of pharmacovigilance and pharmacoepidemiology. Based on the different approaches used to create the BRA during the life cycle of a drug and in the framework of drug regulations, we discuss how both settings are of interest in this assessment. Naturalistic versus randomized evidence During the first half of the 20th century, the evidence lor the therapeutic efficacy of new drugs, in particular anti-infectious

drugs, was often so obvious that the naturalistic observations of therapeutic Inhibitors,research,lifescience,medical successes in treated patients were sufficient to demonstrate efficacy. However, soon the demonstration of the therapeutic efficacy of new drugs became less obvious, and the need to implement a methodology to demonstrate efficacy appeared necessary.7 Inhibitors,research,lifescience,medical The demonstration of drug efficacyis essentially a comparative exercise in which a new drug is evaluated versus a comparator, a placebo, or a NLG919 reference active drug. The clinical efficacy of a treatment is assessed by clinical trials, the

methodology of which has been developed and perfected since the early experiments of Sir Austin Bradford Hill in the 1950s8; the cornerstone Inhibitors,research,lifescience,medical ol clinical trials is the randomization process which ensures that groups ol patients receiving the different treatments are similar. From a statistical viewpoint, the demonstration of efficacy is based on the rejection of the null hypothesis, ie, that there is no difference between the experimental and the comparator treatments. Several Inhibitors,research,lifescience,medical clinical trial designs are used during drug development and generally a couple of randomized

controlled trials should provide a demonstration of the statistically significant superiority of the experimental treatment over the comparator. For example, Inhibitors,research,lifescience,medical the US Food and Drug Administration (FDA) requires at least two phase III pivotal trials with positive results to allow registration of a new drug.9 Regulatory authorities such as the European Committee for Medicinal Product for Human Use (CHMP) from the European Medicines Agency (EMA) regularly publish guidelines on how to evaluate and demonstrate the efficacy and safety of drugs in different therapeutic medroxyprogesterone indications, for example more than 20 CHMP guidelines set the framework for clinical development and clinical trial methodology lor neuropsychiatrie drugs in Europe. Regulatory agencies rely essentially on randomized controlled trials to support the efficacy evidence. The establishment ol efficacy is achieved at the end of Phase III, when the results of the pivotal trials which are key to support the registration process are available.