Transcript Guidelines

Training Workshop:
Training of BE Assessors
Kiev, October 2009
Frequent Deficiencies
Dr. Henrike Potthast ([email protected])
Training workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
Inspection of bioequivalence studies
Critical and major deviations observed during
WHO inspections of CROs by WHO inspectors
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
Introduction
Classification of deviations
„Critical“ deviation means that this can lead to the conclusion that the study is
not of a satisfactory level of compliance with the GCP/GLP.
Several „major“ deviations can lead to the conclusion that the study is not of a
satisfactory level of compliance with the GCP/GLP.
„Minor“ deviations need to be addressed in order to sustained the confidence in
the work of the organization.
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
Critical deviations
Clinical part eg.:
No quality assurance system established (eg.:
at the time of the study);
Consent form not signed by subjects (eg.: case
report form had been lost).
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
The ethics committee is not operating and executing its tasks free
from bias and from any influence of those who were conducting
the trial.
Neither the contract nor the protocol describes the responsibility
for the design of the protocol
Complex language is used in the informed consent forms to be
signed by the subjects ("Stevens-Johnson Syndrome", "toxic
epidermal necrolysis", "erythema multiforme" angiodema,
neuropathy, anaphylaxis, steatosis ).
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
No dosing procedure (eg.: There was no quality assurance system
established at the time when the study was done);
No record of dosing or not sufficiently detailed (eg.: The dosing
form was filled in advance, before dosing: box ticked for Treatment or Reference);
No drug accountability form
or inconsistencies
(eg.: discrepancies between drug dispensed,
dosed and returned).
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
The identity of the medicinal product administered to each
subject at each period of the trial can not be guaranteed due to
insufficient documentation on the dispensing of the product
Discrepancy between the protocol, the consent forms and the
final report regarding the strength of the test product used
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
The batch and the manufacturing
date of the test product mentioned in
the Certificate of Analysis were
different of those indicated on the
shipping letter. Lack of shipping
letters for the reference products.
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Reference
product
Frequent Deficiencies
Case: manufacturer.
Protocol:
Study report:
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
No certificate of analysis or not
sufficiently detailed
(eg.: batch size for the test product
was not mentioned or less than 100000 units)
No record of dispensing or not sufficiently detailed (eg.:
- only a typed form prepared in advance to help the staff for the dispensing;
- no indication of date of preparation, of the operator, no signature of operator,
no mention of double check, no record of line clearance…);
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
No drug testing was performed on the subjects.
Therefore in fact there is no guarantee that the drug
abstinence is respected.
Subject withdrawal due to an adverse event (e.g.
vomiting 4 hours post-dose) without any sufficient
documentation. The decision was not taken by the
investigator until more than 3 h after the event took place
and 6 PK blood samples were unnecessarily taken.
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
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Frequent Deficiencies
Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
Identical ECGs for different Volunteers:
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
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Frequent Deficiencies
Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
The composition of the meals versus protocol is not satisfactory
as e.g. pizza toppings could be chosen by the volunteers.
Consequently the meals are not standardized.
Fasting and meals are not controlled during the study days.
Records of the timing, duration of meals and
amount of food and fluid consumed are missing.
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
Storage condition of blood
samples not monitored. (eg.:
Temperature records were only kept for
one freezer. Proper storage of the
samples was therefore not
documented. During the inspection the
freezer for the blood sample storage
did have a temperature drop to give
alarm. The system had a red light
signal but not the sound signal which
should have been also the case
according to the laboratory personnel).
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
The method of calculating AUC values (linear
trapezoidal method or other, method of extrapolation to
infinity) is not specified in the trial reports and/or
incorrect.
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
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Frequent Deficiencies
Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Blood
sampling
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Frequent Deficiencies
Case: tmax.
Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
The justification of the reintegration is not apparent (and
not acceptable) and there is no source document to prove
that the SOP for manual reintegration is followed (no
signature, no date, no comment of authorized person on
the chromatograms)
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GCP/GLP
Frequent Deficiencies
Case: manipulation
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
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Frequent Deficiencies
Case: remarkable data
Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Analytical
method
- LOQ:
Frequent Deficiencies
Case: LOQ (1).
10 ng/ml, sampling period 96 hours
- AUC0-t: 639 +/- 258 ng.h/ml
- AUCinf: 1367 +/- 379 ng.h/ml
- Cmax: 31 +/- 14 ng/ml
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GCP/GLP
Analytical
method
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Frequent Deficiencies
Case: LOQ (2).
Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
The sample analysis of one subject is coded as “Outlier”
(here: concentration much higher than other subjects for
this time). The repeat analysis shows a different value but
similar to those of other subject at this time. Therefore,
the initial result cannot be left as “outlier”. An explanation
must be provided (mixed samples?) and SOPs should
cover such deviations.
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
Several data found on chromatograms are not consistent
with the final concentration reported by the bio-analytical
laboratory but used for calculations
Only one QC/batch at each concentration (LQC, MQC,
HQC) is processed
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
Bioanalytical part
Critical deviations in %
% critical deviation
Raw data not available
calculation errors
exclusion of QC for P&A
batch acceptance
manual re-integration not
consistent
forged peak
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
Bioanalytical part
Major deviations in %
% major deviation
no fresh CC for LT
QC not adequate tu sub
conc
exclusion of QC for P&A
discrepancies
data/report
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
Use of correction-fluid and overwriting on CRFs and other
raw data.
Lack of documentation on monitoring and auditing
…and more…
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Workshop: Training of BE Assessors, Kiev, October 2009
GCP/GLP
Frequent Deficiencies
THANK YOU
FOR YOUR ATTENTION
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Workshop: Training of BE Assessors, Kiev, October 2009