November 2024 SOCRA Source Journal - Journal - Page 35
investigator only collected the
subject’s initials and printed
name on the informed consent
form, instead of the signature
and date. In some cases, the
clinical investigator did not even
collect an informed consent form
prior to beginning the study. The
FDA found that several subjects
underwent study-related testing
before informed consent was
obtained.
“Failure to ensure that
informed consent was
obtained in accordance with
21 CFR Part 50 [21 CFR
50.20, 50.27(a), and 812.100].
As a clinical investigator, you
are responsible for ensuring
that informed consent is
obtained in accordance with
21 CFR Part 50. No clinical
investigator may involve a
human subject in research
unless the clinical investigator
has obtained legally effective
informed consent from the
subject or the subject’s legally
authorized representative. In
addition, a clinical investigator
shall document informed
consent by the use of a written
consent form approved by the
Institutional Review Board (IRB)
and signed and dated by the
subject or the subject’s legally
authorized representative at
the time of consent.
b. (b)(4). You did not obtain
prescreening written Informed
Consent for (b)(4), (b)(6). For
example, the “Note To File”
dated 7/7/2009 for subject (b)
(6) indicates that the subject
underwent study-related
testing, on 4/9/2008, and that
you did not obtain informed
consent until 4/18/2008.
Also, the “Note To File”
dated 7/10/09 for subject (b)
(6) indicates that the subject
completed all screening
assessments on 2/14/2008
and that you did not obtain
informed consent until
2/15/2008.”
Unfortunately, this NTF
provided a nice timeline for
the major informed consent
errors committed by the clinical
research site. Since this deviation
was escalated in a Warning
Letter, there is a good chance
that the informed consent issues
remain unresolved.
FDA inspectional observations
or FDA Form 483s, Warning
Letters, and responses from
clinical research sites all become
available on the FDA’s website.
Thus, sponsors looking to
qualify sites for their studies
can see these observations.
Quality System Oversight
Quality system alternatives
to NTFs to document study
issues exist (Table 5). Instead of
generating a standalone NTF,
depending on what needs to
be communicated, it may be
possible to create a source
document in the subject’s
昀椀le, such as an additional
drug accountability log or a
drug accountability note. A
monitoring or site visit report
where the issue was 昀椀rst
noted and discussed with the
clinical research site is another
alternative to NTFs, as is
correspondence with the IRB
and regulatory staff.
It may be possible to identify
a location in the Trial Master
File instead of creating multiple
placeholder notes. For example,
a decision can be made to 昀椀le a
regulatory approval document
in the same section of the Trial
Master File as IRB approvals. In
cases like this, it is preferable
to identify the 昀椀ling location in
the Trial Master File rather than
using multiple NTFs.
The quality system alternatives
to NTFs chosen by a clinical
TABLE 5
Problems with NTFs Seen
During Audits
•
•
•
•
Subject’s source
documents
Monitoring or site visit
reports
Correspondence
The Trial Master File
research site depends upon
the documentation generated
and what the site chooses
to do as a whole. Another
suggestion, which is gaining
momentum, is to borrow from
the pharmaceutical and device
manufacturing industries and
implement a corrective action
and preventative action system.
In pharmaceutical and device
manufacturing, it is generally
assumed that some processes
are likely to go wrong and
could affect quality. When that
happens, the quality issues must
be resolved in a timely, effective,
and well-documented manner.
The FDA does have guidance
on corrective and preventive
actions, which are intended to
昀椀x a problem with the overall
system to correct the existing
non-conformity or quality problems and prevent recurrence of
the problem. Corrective actions
and preventative actions can
be more thorough and systemdriven than NTFs. They can also
be paired with risk analysis. For
example, if the clinical research
site identi昀椀es studies that are of
high risk, a preventative action
can be deployed to minimize
those risks. At the end of the
day, however, it is all dependent
on the documentation generated and ongoing practices at
the site.
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