Quality expectations and tolerance limits of trial master files (TMF) - Developing a risk-based approach for quality assessments of TMFs.

This article addresses the question of when a trial master file (TMF) can be considered sufficiently accurate and complete: What attributes does the TMF need to have so that a clinical trial can be adequately reconstructed from documented data and procedures? Clinical trial sponsors face significant challenges in assembling the TMF, especially when dealing with large, international, multicenter studies; despite all newly introduced archiving techniques it is becoming more and more difficult to ensure that the TMF is complete. This is directly reflected in the number of inspection findings reported and published by the EMA in 2014. Based on quality risk management principles in clinical trials the authors defined the quality expectations for the different document types in a TMF and furthermore defined tolerance limits for missing documents. This publication provides guidance on what type of documents and processes are most important, and in consequence, indicates on which documents and processes trial team staff should focus in order to achieve a high-quality TMF. The members of this working group belong to the CQAG Group (Clinical Quality Assurance Germany) and are QA (quality assurance) experts (auditors or compliance functions) with long-term experience in the practical handling of TMFs.

GCP inspections in Germany and Europe following the implementation of the Directive 2001/20/EC.

BACKGROUND: The implementation of the Clinical Trials Directive 2001/20/EC and the Good Clinical Practice Directive 2005/28/EC fundamentally restructured and harmonized the conduct of clinical trials in Europe. GCP inspections - which affect study sites, laboratories, sponsors and contract research organizations (CRO) alike - make up an important part of these regulations. A common understanding of how these regulations apply in daily life is however not always ensured. METHODS: A working group of the Clinical Research/Quality Assurance subcommittee of the German Association of Research-Based Pharmaceutical Companies (VFA) was established to outline the regulatory requirements, the experience gathered with inspections by means of a survey and to set up guidance on how to manage an inspection. RESULTS AND CONCLUSIONS: The survey, conducted with the help of 15 pharmaceutical companies within the VFA, included a total of 224 inspections (74 inspections in Germany, 150 from other European countries). Most frequent findings in and outside Germany were related to "documentation" (40.5% vs. 21.3%), "investigational new drugs" (16.2% vs. 14.7%), "drug safety" (13.5% vs. 8%) and "application for a clinical trial authorization" (5.4% vs. 12%). From a German perspective, key findings of this working group were the necessity for a clear differentiation of responsibilities between national and federal as well as international authorities, a harmonization of inspection procedures and topics, and a clarification of whether pre-study/on-study and pre-approval/post-approval GCP inspections of the federal higher authority are included in the "Zentralstelle der Länder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten" (ZLG) requirements. The survey illustrated, that inspections usually are conducted at the investigational site, and that most of the findings are well known and thus could be prevented by communicating and discussing audit results more intensely within study groups. Again, the survey illustrated, that a harmonization of inspections appears warranted. Finally a code of practice is provided that considers these findings and delivers a basis for a successful inspection whether at the sponsor or the GCP site.