2.10.1 Adverse events, and serious/unexpected adverse events

Definitions
In accordance with the ICH/EU Guideline for Clinical Safety Data Management (ICH, 1994), an adverse event (AE) was defined as any untoward medical occurrence in a patient who received medically prescribed heroin and/or methadone during the study, regardless of whether the occurrence was causally related to the treatment. A Serious Adverse Event (SAE) was defined as

Table 5. Response definition

an AE, which resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, or was a congenital anomaly or birth defect. Lastly, an unexpected adverse event was defined as an AE of which the nature, severity or frequency was not consistent with the currently available published literature or with the information described in Martindale (1997). In addition to these various types of AEs, drug overdoses, psychoses and epileptic attacks were registered separately throughout the study.
The severity of an AE was defined as mild, in case the AE was transient and easily tolerated, moderate, if the AE caused the patient discomfort and interrupted his usual activities, and severe, if the AE caused considerable interferences with the patient's usual activities and was potentially incapacitating or life-threatening. In addition, whereas there is currently no accepted standard international nomenclature to describe the degree of causality between a medication and an event (ICH, 1994), the causal relationship with the experimental medication was defined according to a widely used scale, consisting of the categories "certainly", "likely", "possibly", "certainly not" and "unknown".

Registration and reporting
As described before, all clinically significant adverse events and all serious and/or unexpected adverse events were documented by the treating physician in the patient's medical file on a continuous basis when they occurred, and in the CRF at the two-monthly assessments. All clinically significant AEs had to be subjected to follow-up investigation, and documented until the adverse event had disappeared or stabilized. In case of any serious and/or unexpected adverse event, the event was immediately reported by the local study co-ordinator to the monitoring organization, both by telephone and by sending an SAE-report by telefax. Within 24 hours after receipt of the SAE-report, the monitoring organization sent a written confirmation of the receipt back to the local study co-ordinator, and within 48 hours to the National Research Board of the CCBH. Reports of adverse events which were both serious and unexpected, and which were considered to be at least possibly related to the experimental medication, were forwarded to the National Safety Committee (LVC) (see paragraph 2.7), and to the Central Committee on Medical Ethics within 48 hours of receipt, and within 15 calendar days to the Inspectorate of Health Care of the Netherlands. This report had to be accompanied by information about the involved treatment site, the patient's identifier code, and a detailed description of the adverse event, in terms of its background and circumstances, possible cause, and causal relationship with the experimental medication. In case of a fatal adverse event, the SAE-report was sent to the National Safety Committee within 48 hours of receipt, regardless of a (possible) causal relationship with the experimental medication.