November 2024 SOCRA Source Journal - Journal - Page 32
Using templates for NTFs
saves time, however, clinical
research professionals must
use a template that has been
updated for the current study.
The template should include the
name of the clinical investigator
and the investigational agent
for the current study. If this
information is incorrect, it often
leads to audit 昀椀ndings. Very
often, sub-investigators who
are not on the delegation of
authority log are found on the
NTF. This is an audit observation
that can easily be avoided.
Using an NTF to explain a
poorly written or inconclusive
NTF can also result in an audit
observation. This demonstrates
a lack of Good Documentation
Practice and can also cast doubt
on study data and process
quality. In essence, NTFs
should always follow Good
Documentation Practice.
The following lessons learned
from audits at the author’s
system can help clinical research
professionals write appropriate
NTFs. In one study, four subjects
on the clinical trial were given
incorrect doses of the study
agent. They were dosed per the
clinical research site’s standard
of care practice and patient
weight, not per the protocol. The
protocol stated that the dose is
dependent on the previous dose.
It should remain the same unless
the subject’s weight changed
by 10% or more. This was
reported to the IRB as a protocol
deviation. The IRB determined
that this protocol deviation
“increased the safety risk to
patients.”
The FDA inspected this study.
Seeing this letter from the IRB
led the FDA investigator to
look further through the subject
binders. The FDA investigator
found four NTFs in the
respective subject binders and
32
further questioned the clinical
research site’s dosing calculation
process as well as the training of
the clinical investigator and the
pharmacist on dosing per the
protocol.
The four NTFs provided
information on the dates of
misdosing and the steps taken
to inform the IRB and the
sponsor. They did not, however,
mention corrective actions
taken to prevent the issue from
recurring. “Will retrain staff”
would not have been a suf昀椀cient
corrective action in this case.
Clinical research professionals
created a metric to determine
the correct doses to be given
versus the actual doses that
were given to each of the
subjects and listed the precise
number of times the dosing
error occurred. This ended
up being fewer times than
portrayed earlier. Each time
the dosing error occurred, the
study agent was given at a
lower dose than speci昀椀ed in
the protocol. After meeting
with the pharmacist and the
sub-investigator to understand
the study agent’s toxicity,
medication interactions, and the
risks involved, clinical research
professionals discovered that
the difference in the dose was
not signi昀椀cant enough to impact
subject safety.
While the FDA investigator
was on site, clinical research
professionals provided
this information. The FDA
investigator changed the
misdosing to a less serious
protocol deviation. The FDA
investigator stated that this
information should have been
provided to the IRB and the
sponsor and that regardless
of the impact of the situation,
clinical research professionals
should have received better
communication and training
SOCRA SOURCE © November 2024
from the sponsor on the correct
dosing of the study agent.
Clinical research professionals
should have a dual checking
process to con昀椀rm that subjects
received the correct dose of the
study agent each time. They and
the pharmacist agreed to update
their practices and policies to
include this requirement.
Lessons learned from this audit
include that writing an NTF
does not end the issue. It is
important for clinical research
professionals to do their due
diligence in 昀椀nding the root
cause of an issue, identify the
impact of the issue on subject
safety, and then report accurate
and complete information
to the IRB, the sponsor, and
all agencies involved. Also,
corrective and preventative
actions must be implemented
and the implementation must
be documented. Other checks
and balances must be in place
for that note, or a follow-up
note, that provides the complete
picture to the viewer, whether
that is an internal staff member
or an FDA investigator.
The next example is related to
redundant NTFs found during an
audit. Subjects were supposed
to undergo a biopsy at the end
of the study when they are off
treatment and the disease has
progressed. This biopsy was
not completed for any of the
subjects enrolled at this clinical
research site. NTFs were 昀椀led
in each subject binder stating
that it was not clinically feasible
for the clinical investigator to
perform the biopsy.
This was also recorded as a
protocol deviation each time
and reported to the IRB and
the sponsor. The IRB and the
sponsor had no problem with
this. The FDA investigator,
however, was concerned that
