Good Clinical Practice: A Question & Answer Reference Guide - May 2016 - 553

GCP and Clinical Research Standards in the European Union
"Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted
outside of the EU/EEA and submitted in marketing authorization applications to the EU Regulatory Authorities,"
EMA/121340/2011, of 16 April 2012.
Because Articles 23 to 30 of EU 2005/28 are not found in the CTR, an implementing act will be produced to
cover these requirements (as required by Article 78 in the Regulation) through an Implementing Act. This will
ensure that there is a legal basis for inspections and qualifications of inspectors.
18.7 Q. To what extent have EU GCP inspections been harmonized?
A. The EU published a range of guidance documents on GCP inspections in mid-2008 and these documents
are updated regularly. The guidances contain common provisions for the member state authorities on how they
should conduct inspections. The documents cover the communication of findings, provisions for inspections at
investigator sites and at clinical laboratories, checks on computer systems, and inspections of sponsors and contract
research organizations.
They also provide guidance on the preparation process for GCP inspections, and for the preparation of inspection
reports. For instance, at investigator sites, inspectors should identify (and verify) the independent ethics committee
(IEC) and check whether it provides a statement that the site is organized and operates according to GCP and
applicable laws and regulations. They should determine whether IEC approval was obtained before the trial was
initiated and whether the approval clearly identifies the trial, the investigator, and the documents reviewed (and
their versions). Further, they should determine whether the coordinating investigator or sponsor has maintained
copies of all reports submitted to the IEC when the trial was initiated. Inspectors should also check on monitoring
and follow-up by the sponsor, in terms of the number of visits at the site, scope and dates of the visits, and
content of the monitoring visit reports. Especially the issue of the "oversight" exercised by the sponsor on service
providers, investigators and other key stakeholders is at the focus of inspections in Europe. In fact, most European
inspectors follow a systems' audit approach rather than a "classical" data verification methodology. Similarly, they
should assess arrangements for obtaining informed consent from subjects, and should check, through appropriate
means, e.g., source data verification, whether the investigator's team conducted the clinical trial according to the
approved protocol and its amendments. In assessing whether the sponsor or CRO is providing quality assurance
and quality control systems for its clinical trials, inspectors should assess if clinical research activities are staffed
with sufficiently qualified and trained personnel for each area. They should review the organizational charts that
identify the key personnel in each area, the independence of the quality assurance unit, and the job description,
qualifications and training of the individuals involved at any stage of the clinical trial process. Inspectors should
also check the audit system and whether it includes audits of key clinical trial processes, audits of contractors
and subcontractors, processes for communicating and addressing audit findings, and procedures for dealing with
serious or persistent non-compliance.
For all inspections, an inspection plan should be established during the preparation period. The emphasis of
the inspection may vary depending on whether or not the inspection is related to the assessment of a marketing
authorization application, to the routine surveillance of clinical trials performed in the member states, or to other
purposes. But before every inspection, an opening meeting should introduce the inspectors to the organization
being inspected, and explain the regulatory framework for the conduct of the inspection. The inspectors should
use this meeting to identify the distribution of duties and functions for the conduct of the trial in the organization
being inspected, and to review the scope and the objectives of the inspection with the staff. The names and titles of
persons interviewed or present during the inspection meetings and the details of the inspected organization should
be documented. If access to the records or copying of documents is denied for any reason or there is any withholding
of documents or denial of access to areas to which the inspectors are legally entitled, these refusals should be
documented and included in the inspection observations. In this context it should be noted that in many member
states, e.g. UK, inspectors have the legal right to request any document or evidence needed for an inspection. This
includes but is not limited to access to sponsors' audit reports. The latter, however, is still an exception. At the
end of the inspection, the inspectors should hold a closing meeting with the staff of the organization inspected to
present their findings. They should ensure that the results of the inspection are clearly understood and that there are
no misunderstandings. Issues that require follow up should be addressed, including any additional documents that
may need to be sent to the inspection team.
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Table of Contents for the Digital Edition of Good Clinical Practice: A Question & Answer Reference Guide - May 2016