10 Any new observation of efficacy in subgroups of patients by serendipity will need

to be confirmed by randomized evidence obtained in Phase Illb trials, in order to obtain an extension of the indication on the drug label. In the perspective of drug efficacy #see more randurls[1|1|,|CHEM1|]# demonstration, the naturalistic studies represent a weaker design in terms Inhibitors,research,lifescience,medical of clinical and statistical quality and power. Although a comparison between an active treatment and a comparator can still be done in a naturalistic setting, such a setting does not permit control for all sources of bias in the estimation of efficacy because of the absence of randomization. The randomized evidence is the support lor demonstrating the benefits expected in BRA for the majority of drugs. There are rare exceptions to this rule, either due to the scarcity of cases or the terminal

Inhibitors,research,lifescience,medical stage of an incurable illness, or because of an imminent medical threat to the population due to infectious agents,11 which could justify omitting proper clinical trials. In cases of threat of a pandemic infectious disease, it could be necessary to market drugs or vaccines despite limited Inhibitors,research,lifescience,medical information from randomized clinical trials; in such cases, there would also be little to no information based on naturalistic observations, and the decisions to administer the therapy in an emergency would be based on surrogate outcomes. Another situation where naturalistic observations might influence the BRA would be when the efficacy of a drug, as demonstrated in randomized clinical trials, did not seem to be maintained in the clinical setting; for example, Inhibitors,research,lifescience,medical the clinical benefit Irom psychotropic drugs seems to have declined over the last decades. The evaluation ol the safety

profile of a drug is more complex than the demonstration of its efficacy. Clinical trials are designed and powered to demonstrate the efficacy of the drug; although Inhibitors,research,lifescience,medical a lot of safety information is collected during randomized trials, this information covers essentially frequent ADRs, or more exactly the frequent adverse events rather than drug reactions (as the causal relationship between events and the taking of the drug is not yet established). A minority of trials are for designed specifically for the assessment of safety, such as trials which assess ECG changes due to drugs expected to affect cardiac electrical conduction.12 Indeed, the clinical development is limited in terms of patient exposure and duration of exposure: only a few thousand patients receive the drug during the clinical development, most ol these during a relatively short period. Common ADRs can be identified during the clinical development, but rare reactions, with frequency less than 0.1%, are generally not identified. It will require the exposure of 10 000 patients or more in order to detect rare serious ADRs.