definiens: means any untoward medical occurrence in a patient or clinical investigation subject, which results in any unfavorable and unintended sign . symptom, or disease temporally associated with the use ora medicinal product, whether or not considered, related to the medicinal product . All noxiOU'l aod unintended responses to a medicinal product related 10 any dose should be considered advcr!oe drug reactions . Responses to a medicinal product means that a causal relalionship beTween rhe product and AE is at least a reasonable possibility ( i.e., the rel : ationship can not be ruled out or can not be dett'nnined ) . The failure of a Product to locali7e as e. '<peclcd shall not be dttm('(j an /I.E, whereas a significant failure ofex~ ted phannacologk acri(lO would be considered an AE