A broad range of measures was taken to maximize the quality of the study data. As described earlier, the study was conducted in accordance with the ICH/EU guidelines for Good Clinical Practice (ICH, 1996), and the study protocols, patient information form, and informed consent form and procedure were submitted to and approved by the Central Committee on Medical Ethics of the Netherlands, prior to the start of the study.

Data collection and training
In each participating study site, the data were collected by independent research teams. The study data were treated confidentially and processed anonymously, and were not made available to the treatment staff. In addition, the data were collected by means of standardized instruments and assessment procedures, and were documented in a standardized paper Case Report Form.
All members of the local treatment and research teams received extensive training in GCP by the independent monitoring organization. The research teams were trained in the administration of the questionnaires and interviews, and received Go back or Close Windowster training sessions throughout the course of the study. In addition, comprehensive Dutch manuals were available for the assessment and scoring procedures of each instrument and supplement.
All study procedures relevant to either the research teams, the treatment staff or both, were outlined in a comprehensive manual, which contained Standard Operating Procedures (SOPs) for a broad range of topics, including the general study design, the tasks and responsibilities of all parties involved, the selection and randomization procedure, the treatment aspects (e.g. the requirements for the treatment unit, dose-schedules for injectable heroin, inhalable heroin, and methadone, drug accountability), and the assessment aspects (e.g. time-frames and planning of the assessments, maximizing the co-operation of participants, collection of urine samples).

Co-ordination
Regular meetings were held between the CCBH and all local study co-ordinators, local treatment co-ordinators, and local treating physicians, each in separate group meetings. These meetings focused on general aspects (e.g. explanation of the study design, treatment regimen, drug accountability procedures), as well as on specific topics which became relevant in the course of the execution of the study (e.g. termination of the experimental treatment for individual patients at the end of the experimental study phase), and were meant to provide a platform to instruct and co-ordinate the local teams on a central level - in order to enhance the quality and consistency of the treatment and assessment procedures across the study sites and throughout the study-period - and to discuss the rationale and consequences of the procedures - in order to improve the acceptance of all study and treatment procedures. In addition, the local treatment sites were visited monthly by the study co-ordinator of the CCBH, both to check whether the procedures were conducted in accordance with the study protocol and SOPs, to discuss possible difficulties, and to give directions for solutions.

Monitoring
The study was monitored by a GCP-certified external independent monitoring organization. The monitor visited each treatment site and local research team every two weeks, during which the treatment and data collection procedures were checked. These checks included verification of the presence and correctness of all informed consent forms, 100% verification of the information in the first CRF (phase I, day 1) with that in the existing medical files and other source documents, 100% verification of the inclusion and exclusion criteria at baseline, and of the primary outcome data at each following assessment-point, and 20% verification of the other information recorded in the CRFs. In case of an incomplete, inconsistent or incorrect CRF, the monitor consulted the responsible person - i.e. the treating physician or the local study co-ordinator - and attempted to resolve the problem. In addition, the monitor observed and checked the drug accountability procedures at each study site, and the registration and reporting of serious (medical and public order) adverse events.

Data management
The information recorded in the CRFs was entered into a computerized database and validated by an external data management organization. Data entry was conducted independently by two data entry typists, using the Clintrial software program. The information entered into the database was subsequently checked according to a pre-established validation plan on the occurrence of missing values, incorrect values, and inconsistencies, with regard to the inclusion and exclusion criteria, the time frames of the assessments, and the primary outcome variables. In addition, all text fields pertaining to concomitant medication, medical history and adverse events data were checked on spelling errors and unclearness. In case of error messages, the CRF was checked manually by the data manager. Remaining errors were sent as queries to the external monitoring organization, and after resolution corrected in the database according to the answers to the queries. After having resolved all queries in a particular dataset (e.g. the patients' baseline values on the SCL-90), the data management organization sent the dataset to the CCBH as a SAS datafile.

Audits and inspections
Throughout the study, several Clinical Quality Assurance (CQA) audits were conducted by the CQA auditor of the independent monitoring organization to assess the study conduct compliance with the protocol, regulations and guidelines for the conduct of clinical trials. These included the ICH/EU guidelines for Good Clinical Practice (ICH, 1996), Good Manufacturing Practices (GMP), the Declaration of Helsinki (1989), and the Dutch Law on medical-scientific research in humans (WMO; Ministry of Health, Welfare, and Sports, 1998). The audits included a visit to the study facility, interviews with the study site personnel (both treatment and research staff), a 100% review of the regulatory documentation and informed consent forms, and a 100% review from a 20% random sample of the total number of patients enrolled in the study on the study site. Upon completion of the audit, the audit findings and recommended corrective actions were communicated to both the National Research Board of the CCBH and the external monitoring organization.
In addition, the Inspectorate of Health Care of the Netherlands conducted inspections at all study sites to assess the compliance of the study conduct and procedures with the protocol, manual, and regulations.
Lastly, a study audit was conducted by an external CQA auditor, independent from the external monitoring organization. This audit consisted of both a system audit, to assess and to evaluate whether the study and its procedures were conducted in accordance with the protocol, regulations and GCP-guidelines, and a late study audit, to evaluate the quality of the collected data.