The inspection in the context of clinical trials may cover good manufacturing practices (GMP) as regards the manufacturing of the investigational medicinal products (IMP) or good clinical practice (GCP) for the conduct of clinical trials.
Two corresponding documents are dealing with these inspections:
Implementing Regulation (EU) 2017/556 of 24 March 2017 on arrangements for GCP-Inspections:
This Regulation lays down detailed arrangements for GCP inspections procedures and requirements regarding training and qualifications of GCP inspectors. The sponsor of a clinical trial and the investigator are to ensure that the clinical trial is conducted in accordance with the principles of GCP. Compliance with the GCP principles, including with standards relating to data integrity, is to be verified by means of inspections. Inspectors shall have the ability to make professional judgments in relation to the compliance with applicable legislation and guidelines and shall be able to assess data integrity.
Commission Delegated Regulation (EU) 2017/1569 of 23 May 2017 on arrangements for GMP-Inspections (as regards IMPs): Ensures conformity with GMP for IMPs and makes provisions on inspections. Regular inspections should be carried out as referred to Regulation (EU) No 536/2014 (CTR) and third country manufacturers should be inspected at least if there is a suspicion that the IMPs are not manufactured by applying quality standards at least equivalent to those applicable in the EU. Inspections may be unannounced and Inspectors shall be empowered to examine any documents relating to the object of inspection, make copies of records or printed documents and print electronic records.
In clinical trials, usually large amount of data is collected and this data is more and more electronically recorded and processed. The check of the integrity of data is mandatory and is usually performed by the clinical monitor who, in the past, preferentially reviewed only the documentation, but not the history of data entries. Particular emphasis should be put on the hybrid systems, where data are manually transferred from paper to the electronic application, i.e. from the case record forms (CRFs), a process which is very error prone. If electronic systems (eCRFs) are used for the data entry by the medical doctors involved in the clinical study, the clinical monitor may need to review the correctness of the electronic data, i.e. if data was modified or “cleaned” after the first entry.
Furthermore, the European Medicines Agency (EMA) recently published their new guideline on Content, Management and Archiving of the (e)TMF which will come into effect on 18th June 2019. According to the guideline areas to consider during quality checks and review include the following:
- Validation of the eTMF, with formal procedures in place to manage this process,
- Audit trail review ,
- Routine QA measures, e.g. system audits of eTMF-management processes (sponsor),
- Ensure the eTMF is readily available and directly accessible to the competent authority, e.g. for inspection purposes (sponsor).
In addition, sponsors contract out an increasing number of tasks in clinical trials. During inspections of commercial as well as academic trials, an increasing amount of deviations from GCP standards have been identified by the inspectors in view of sub-standard contractual arrangements and related procedures. Special consideration should be given on training and quality systems. Experience suggests that vendors accepting tasks on electronic systems are frequently knowledgeable on IT systems and sometimes on data protection legislation, but not necessarily on GCP requirements, quality systems, etc.
The challenges with these tasks are frequently underestimated. The risk-based approach concepts of the new ICH E6 (R2) GCP Guideline, which is valid in the EU as of June 14, 2017, are also applicable for data integrity. Additionally, the revised ICH E6 Guideline contains detailed requirements regarding validation of computer based systems used in clinical trials.
Therefore it is necessary to know the risks regarding data integrity and computerized systems in GCP area and to establish risk management measures to implement reasonable and efficient GCP/GMP compliant global data governance Systems.