To add to the difficulty, the efficacy of a drug is well measured in randomized trials, while the risk of a specific ADR can only be assessed once this ADR has been observed: as long as this is not the case, the ADR remains hypothetical, based on some supposed biological mechanism, or even ignored when the ADR is idiosyncratic. For example, the risk ol agranulocytosis with clozapine became obvious when the first case series were recorded,29 not at the time of registration.

The potential for a given risk based on the known mechanism of action of the drug (or on that of the pharmacological class of the drug) also enters Inhibitors,research,lifescience,medical into the balance, and this potential risk can only be quantified with much uncertainty. The dimension of time is central to the evaluation of risks, and the BRA of a drug starts during the preclinical development, to continue during the clinical development and the marketing phase. Once on the market, the first years are critical for Inhibitors,research,lifescience,medical a drug

BRA, as the exposure to the new drug increases considerably in terms of number of patients, of duration Inhibitors,research,lifescience,medical of exposure and of heterogeneity of patients compared with the selected patient population included in the clinical trials. However, even the first few years on the market are sometimes not enough to establish a full BRA: the longterm exposure can be critical, as certain ADR may be observed only alter an exposure ol several years, such as cancers or chronic organ toxicity. Immunodepression-related lymphoprolilerative

disorders take about 5 years Inhibitors,research,lifescience,medical to appear,30 and liver cirrhosis may appear only alter decades of treatment with methotrexate,31 Delayed toxicity can be observed in the offspring of patients exposed to a drug, as seen with vaginal Inhibitors,research,lifescience,medical towards adenocarcinomas in daughters of women who had taken diethylstilbestrol during pregnancy.32 The information gathered from randomized studies done during the clinical development corresponds to a drug exposure of limited duration: at this stage of development, the long-term exposure Batimastat to the drug (1 year or more) is restricted to a limited number ol patients – a lew hundred. The International Conference on Harmonisation (ICH) guideline Ela on the long-term safety requires only 100 patients followed up for 1 year in a registration dossier.33 Only the naturalistic observations of large-scale and long-duration post-marketing exposure will bring the information on rare and/or delayed ADR. The BRA, based on randomized except evidence during the initial clinical development phase, becomes mainly based on naturalistic evidence during the post-marketing period, ie, on evidence from pharmacoepidemiological observational studies and the pharmacovigilance system. The BRA remains mainly a qualitative exercise.