(e.g. significant trends in laboratory data or new
preclinical data) that might have an impact on the
risk assessment of the study. Safety events may
necessitate an update to the investigator brochure,
the protocol and CRF, and the information sheet
and consent form.
12.5 Collecting data
with integrityCollecting data that are accurate, honest, reliable
and credible is one of the most important objectives
of conducting clinical research. It is difficult to
achieve. However, in general, data in CRFs are
not credible to the regulators unless they can be
supported by the ‘real’ documents (i.e. the source
documents maintained at the study site for the
clinical care of the study subject).
Source data verification
Source data verification is the process of verifying
CRF entries against data in the source documents.
Source data verification is only carried out at the
study site, usually by the sponsor/CRO monitor
(auditors will also conduct source data verification
on a sample of CRFs; inspectors may conduct
source data verification on a sample or all CRFs).
Source documents (and the data contained
therein)comprise the following typesofdocuments:
patient files (medical notes where summaries of
physical examination findings, details of medical
history, concurrent medications/devices and dis-
eases are noted), recordings from automated instru-
ments, traces (e.g. ECGs, EEGs), X-ray films,
laboratory notes and computer databases (e.g. psy-
chological tests requiring direct entry by patient
onto computers or direct entry of patient informa-
tion onto computers by physicians).
The primary purpose of source documents is
for the care of the study subject from a clinical
perspective: the primary purpose of CRFs is to
collect research data. CRFs (and other data col-
lection forms) generally cannot substitute as
source documents. Data entered in CRFs should
generally be supported by source data in source
documents, except as specifically defined at the
beginning of the study. Nevertheless, some data
entered in CRFs may be source data (e.g. multiple
blood pressure readings, psychiatric rating
scales, etc.) and would not be found elsewhere.
This may be acceptable, if these data would not
normally be entered in medical records, and if
knowledge of such data is not required by the
investigator or other clinicians who concurrently
or subsequently treat the study subject (the pro-
tocol should specify which data will be source
data in the CRF).
How much information is expected to be docu-
mented in source documents? This is a difficult
issue, but one that must be discussed and resolved
before the CRFs are completed. Some guidelines
are provided in Table 12.9.
Direct access to source documents is required
for all studies – direct access means monitors,
auditors, other authorized representatives of the
sponsor/CRO and inspectors are permitted to
view all relevant source documents needed to ver-
ify the CRF data entries. Other restricted methods
of access to source documents (e.g. ‘across-the-
table’, ‘back-to-back’, ‘interview method’) are not
acceptable, as they do not allow proper verification
of the data in CRFs. To ensure direct access, the
study subject consent form must clearly indicate
that permission for access has been granted by the
study subject.Other review to assure data integrity
After retrieval from the study site, there are further
means of assessing CRFs. First, there is the initial
review at the sponsor/CRO premises: this process
is sometimes referred to as ‘secondary monitor-
ing’. Thereafter, review by the data management
department is another extremely important means
of quality control. It is a lengthy and complex
process and there are few guidelines and regula-
tions for reference. These processes will inevitably
result in queries about the data. It is critical that
all data review procedures be prompt. As time goes
by, it becomes more and more difficult to correct
data. Slow processing usually means that data lose
credibility.150 CH12 GOOD CLINICAL PRACTICES