EORTC – Lessons learned from National Competent Authorities Inspections

Both EORTC Headquarters and EORTC investigators are increasingly subject to routine Good Clinical Practice Inspections by Competent Authorities. Such inspections were foreseen by Directive 2001/20/EC, and the setting of the inspections was given more detail by Directive 2005/28/EC.

What are inspections?

As defined by the Directives, these inspections consist of a Competent Authority taking the action to conduct an official review of documents, facilities, records, quality assurance arrangements, and any other resources that it deems to be related to the clinical trial. These materials may be located at the site of the trial, at the sponsor’s and/or contract research organization’s facilities, or at other establishments which the Competent Authority sees fit to inspect.

The objectives of these inspections are to ensure that clinical trials are conducted according to the approved protocol, the applicable national legislation, and to ethical standards. This ensures that patient safety is guaranteed.

Since the trial master file is the main source of information for the inspectors, this needs to be reviewed prior to the start of the inspection. Any written procedures that were followed in order to conduct the trial can also be subject to inspection.

Because the inspectors rely on written documentation, it is extremely important to document all trial related activities. Documentation is everything; if it is not documented, then it is considered that it was not done.

Important findings from the latest inspections in Switzerland and the United Kingdom in which the EORTC was involved.

Investigational Medicinal Product (IMP) management

Findings here were related to:

• drug accountability not maintained or incomplete;
• IMP labeling (mainly related to reconstituted drugs) was missing reference to study protocol and investigator;
• use of commercial stock;
• missing prescriptions;
• insufficient control on the expiry dates (when providing an oral drug over longer time periods, the expiry date should cover the entire period).

IMP management requires careful documentation of all actions/activities performed to the IMP and requires good communication between the pharmacy and the rest of the study team at the hospital as well as EORTC Headquarters.

Protocol Compliance

Findings here related to

• adherence to the eligibility criteria, patients entered which fall outside the limits foreseen in the protocol;
• interpretation of the protocol.

We therefore ask, that when you are confronted with situations not foreseen in the protocol, you should request a clarification from the EORTC Project Manager (PM) and/or Clinical Research Physician (CRP). Please keep in mind that the EORTC Headquarters should always be the first line of communication.

Safety information

Findings here related to:

• no review or evidence of review of SUSARs (Suspected Unexpected Serious Adverse Reaction) or other safety alerts by the investigators;
• no review or evidence of review of the IB (Investigator Brochure)  and its updates.

We therefore ask you to carefully consider this updated safety information for the trials you are running.

The take home message is that we should all be “inspection ready”. In practice, preparation is always necessary, and this preparation can entail an intensive workload for everyone involved both in advance as well as following the inspection.

Hopefully, these frequent inspection observations might help to prevent them from occurring at your hospital.

Below please find inspection news from some Competent Authorities:

UK – MHRA:
Good Clinical Practice: The inspection process

France – afsapps:
Inspections par l’unité inspection des essais cliniques (UIEC) de l’Afssaps
Essaie cliniques – Médicaments et produits biologiques

Germany – BfArM:
Bundesinstitut für Arzneimittel und Medizinprodukte

The Netherlands – CCMO:
Onderzoek naar de PROPATRIA-studie. Lessen voor het medischwetenschappelijk onderzoek met mensen in Nederland
CCMO – Rapport over de toetsing van de PROPATRIA‐studie door de Medisch Ethische ToetsingsCommissie van het Universitair Medisch Centrum Utrecht

Belgium – FAGG / AFMPS:
NL: Goede Klinische Praktijken (GKP)
FR: Bonnes Pratiques Cliniques (BPC)
EN: Good Clinical Practice (GCP)

Cindy Wyns and John Bean