site, in preparation for an investigator site audit or
at trial termination and before archiving to ensure
completeness of the essential documents as per
ICH GCP (1995).
Complete, consistent and accurate trial docu-
mentation is the basis for any inspection by regu-
latory authorities or sponsor/client audit and is a
proof that the study was conducted according to
GCP regulations, the trial protocol and SOPs. The
TMF plays a vital role in providing confidence to
auditors and inspectors that the clinical data are
valid and that the trial was conducted properly.
Although it may be possible in studies with only
few investigator sites to conduct a 100% review of
the TMF contents, large trials require a sampling
approach.
TMF audits may be conducted to review the
filing system for trial documentation. Combining
the TMF audit with an assessment of the archiving
system allows evaluating the retrieval procedures
of trial documents to ensure that the documents are
accessible at any time within the agreed archival
period.
Investigator site audit
Investigator site audits are probably the most fre-
quent type of audits conducted by clinical QA
departments and, therefore, deserve particular
attention. The purpose of investigator site audits
is to assess compliance with the GCP regulations
(with a focus on the country-specific regulatory
requirements) and the protocol. Further, thesafety
of the trial participants, the ethical conduct of the
trial and the validity, completeness and accuracy of
the data collected and recorded are verified during
the audit.
Preparing for the site audit requires thereview of
key trial documentsbefore visiting the site for the
on-site part of the audit. The QA auditor should
review at least the trial protocol (and amendments),
the current investigator’s brochure (to the extent
necessary). Ideally, the following documents
should be studied as well before the audit: any
site-related documents including the IEC submis-
sion and approval, approved informed consent
form used at the site, monitoring reports for the
site, serious adverse event (SAE) reports and ship-
ment forms of IMP and study materials, previous
audit reports related to the site and relevant SOPs
followed for clinical monitoring.
At the investigator site, after anopening meeting
to introduce the audit team, the auditees and the
audit process,interviewswith the site staff are
conducted to determine procedures followed for
recruiting and consenting trial subjects, method of
recording source data and maintaining source
documents, communication and interaction
between site personnel, sponsor and any external
providers. Also, delegation of responsibilities and
tasks is discussed at this stage of the audit.
During the time on site,facilities for storage and
archivalofIMPs, biological samples and trial-
specific equipment are reviewed. These facilities
should be secure and protect the items stored
against loss or deterioration. Access should be
restricted to authorized personnel and should be
controlled. Storage and archival facilities for docu-
ments (e.g. investigator binder, trial records, CRFs
and source data) should be secure for the duration
of the trial and the archiving period. Storage facil-
ities for IMPs must be environmentally monitored
(e.g. temperature, light and humidity) and storage
conditions must be recorded to allow for retrospec-
tive assessment of storage conditions. Biological
samples must be kept at required temperatures, for
example in the refrigerator or in –20Cor–80C
freezers. Regular maintenance, cleaning and cali-
bration is required and should be documented. If
any specific equipment is required for the trial,
records should be verified regarding maintenance,
calibration, quality control and SOPs.
Another important component of investigator
site audit is toreview the investigator site filefor
completeness to verify if all trial-related docu-
ments are available at the site. Chapter 8 of ICH
GCP (1995) lists the documents to be expected at
the site. In addition, country-specific regulations
may require additional documents to be included,
such as the FDA form 1572 ‘Statement of Investi-
gator’ for investigators involved in Investigational
New Drug (IND) trials. A particular focus of the
document review is placed on ethics committee
correspondence and approval; regulatory autho-
rity correspondence and notification/approval;170 CH13 QUALITY ASSURANCE, QUALITY CONTROL AND AUDIT