November 2024 SOCRA Source Journal - Journal - Page 34
At the April 2002 monitoring
visit, the 昀椀ndings identi昀椀ed
at the investigational site
included inclusion of ineligible
subjects into the study, lack of
documentation to show that
subjects had the disease under
study, visits not within the
protocol required time periods,
and continued problems
with informed consent
documentation.
At least 89 memos to 昀椀le
were generated during the
April 2002 monitoring visit
to address these violations.
As noted above, generation
of memos to 昀椀le after all
subjects have completed the
study does not adequately
secure compliance of a
clinical investigator.
In summary, our investigation
found that the sponsor
did not adequately secure
compliance of the clinical
investigator. In addition,
the sponsor’s method for
securing compliance, (i.e., the
generation of more than 125
memos to 昀椀le for protocol
and informed consent
deviations noted at the
site) was not adequate.”
In this case, the NTFs only
documented the study practices
for the auditors. The work
done to create all of those
memos would have been better
spent training clinical research
professionals and creating a
robust quality system. Also,
simply documenting a mistake
means nothing during the FDA
inspection. This Warning Letter
is full of subtle and not-so-subtle
ways a clinical investigator can
fudge the system. In this case,
the clinical investigator served
a jail sentence for fraud.
The FDA issued the next
Warning Letter to a sponsor
for misuse of NTFs, among
other issues. The FDA cited the
34
sponsor for not maintaining the
stability of the IV drug throughout
the study for all 39 subjects.
A monitor had noticed the
issue. The sponsor had tried
to write an NTF to address the
issue, however, the FDA did
not consider the issue to be
addressed. The FDA stated
that the NTF that was 昀椀nally
written after completion of
subject enrollment only stated
that IV drug stability had been
maintained according to the
label, which did not provide
suf昀椀cient detail to ensure that
temperature stability conditions
for the drug were maintained
adequately.
The FDA also questioned why
the sponsor had chosen this
clinical research site despite
a recommendation from the
monitor to not use the site.
There was a memo in the 昀椀le
stating that the supervisor at the
contract research organization
(CRO) overruled the monitor’s
recommendation. The FDA
found that the sponsor failed to
participate in selection of the site
and did not review and address
the monitoring report.
“Failure to ensure proper
monitoring of the clinical
investigations [21 CFR 312.50;
312.56(a)].
FDA notes that in your
response dated June 24, 2008
you state that the issue was
recorded in the unblinded
monitoring visit reports
dated 27 January 2006 and
25 September 2006, along
with documentation that the
monitor requested completion
of the work-sheets, and that
the site generate a Memo
to File that documented
the IV temperature stability
conditions for previously
enrolled subjects. However,
the issue should have been
SOCRA SOURCE © November 2024
addressed again prior to the
25 September 2006 unblinded
monitoring visit. The Memo
to File that was 昀椀nally written
on 16 November 2006,
after completion of subject
enrollment at the site, stated
only that “IV stability has
been maintained according
to the IV label, which states
start/昀椀nish time and the
expiry time of the infusion,
and the patient number.” This
statement does not provide
suf昀椀cient detail to ensure
that temperature stability
conditions for the drug were
maintained adequately.
In your response to the
Agency, dated June 24,
2008, you stated that when
you questioned (b) (4)
representatives regarding
why this site was selected
despite the study monitor
recommendation to
not use the site, (b) (4)
provided a memo dated
June 3, 2008 that stated
the CRO supervisor
overruled the study monitor
recommendation. According
to the (b) (4) Work Order,
however, the sponsor, not
(b) (4) was responsible for
昀椀nal approval of sites for
participation in the study.
Furthermore, the sponsor
failed to make this inquiry
until after the FDA inspection.
Based on your response, it
appears that you either failed
to actively participate in
selection of the site or failed
to review and address the
study monitoring report that
recommended the site not be
used.”
The last FDA Warning Letter
was issued to a speci昀椀c clinical
investigator for misuse of
NTFs. The sponsor had 昀氀agged
concerns about the clinical
research site’s informed consent
practices, where the clinical
