Directive 2001/20/EC on Good Clinical Practice in Clinical Trials

Abstract

The final version of the European Union (EU) Clinical Trials Directive (2001/20/EC) was published in the Official Journal of the European Communities on 1 May 2001,[1] and is also available on the Commission’s website.[2] The full title is Directive 2001/20/EC of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Member States were required to prepare national provisions for complying with the Directive by 1 May 2003 and bring the provisions of the Directive into force by 1 May 2004. Non-compliance with the requirements of the Directive would become a criminal offence once the Directive has been adopted into national laws and implemented. The Directive required the European Commission to issue guidance about the requirements of the Directive and how they should be applied. Final versions of the guidance documents were released in April 2003.[3] What is summarised here are the key issues in the Directive and Guidance with reference to pharmacovigilance, highlighting potential implications. The key issues for pharmacovigilance include reporting requirements, expedited reporting, investigator responsibility, sponsor responsibility, safety communication to investigators, annual safety reports, Eudravigilance – clinical trial module/electronic submission of suspected unexpected serious adverse reactions (SUSARs) and pharmacovigilance audit as part of Good Clinical Practice (GCP) audit. The Directive and Guidance have introduced additional requirements, which will have resource implications for pharmacovigilance and data management departments. Annual safety reporting (line listing/summary tabulation of all serious adverse reactions [SARs] and a report of subjects’ safety) would be required. The report on subjects’ safety is a risk-benefit evaluation of the trial concerned and requires more information than that collected for serious adverse events (SAEs). The implication is that safety data (other than SAEs) and denominator data to aid risk-benefit evaluation should be collected in real time, reviewed and entered on the relevant databases ready for the annual report. The quality of annual reports would depend on what data are available and the skills and expertise of staff reviewing and interpreting the data. The skills of highly qualified and experienced staff including physicians, epidemiologists and statisticians would be needed. Emphasis is shifting from processing and reporting individual cases of SAEs to ongoing cumulative review of safety data, interpreting safety data, identifying risk at early stage and communicating risk in a timely manner. Where a sponsor conducts several clinical trials with the same investigational medicinal product (IMP), the annual safety report should be based on the experience from all clinical trials performed by the sponsor and all available data. For ease of production of annual safety reporting and safety monitoring, centralising pharmacovigilance activities for all studies of a single IMP including setting up a central pharmacovigilance database earlier on in the development programme should be considered. The use of ‘all adverse events’ in the Guidance is confusing: “The sponsor has to keep detailed records of all adverse events (AEs) reported to him by the investigator(s) and perform an evaluation with respect to seriousness, causality and expectedness”. Some companies have interpreted this to mean that real time reviews as currently performed for SAEs would be required for non-serious AEs. This would have major resource implications for pharmacovigilance departments.