Transcript GCP

WHO Workshop on Assessment of
Bioequivalence Data
Addis Ababa, 31. August – 3. September
Frequent Deficiencies
Dr. Henrike Potthast ([email protected])
WHO Workshop on Assessment of Bioequivalence Data, Addis Ababa, 31. August – 3. September 2010
GCP/GLP
Frequent Deficiencies
Inspection of bioequivalence studies
Critical and major deviations observed during
WHO inspections of CROs by WHO inspectors
WHO Workshop on Assessment of Bioequivalence Data
2 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Frequent Deficiencies
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 GCP/GLP
standards.
Several „major“ deviations can lead to the conclusion that the
study is not of a satisfactory level of compliance with GCP/GLP
standards.
„Minor“ deviations need to be addressed in order to sustaine the
confidence in the particular CRO.
WHO Workshop on Assessment of Bioequivalence Data
3 | 31. August – 3. September 2010, Addis Ababa
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

Case report form had been lost
WHO Workshop on Assessment of Bioequivalence Data
4 | 31. August – 3. September 2010, Addis Ababa
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 ).
WHO Workshop on Assessment of Bioequivalence Data
5 | 31. August – 3. September 2010, Addis Ababa
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 Test or Reference);
No drug accountability form
or inconsistencies
(eg.: discrepancies between drug dispensed,
dosed and returned).
WHO Workshop on Assessment of Bioequivalence Data
6 | 31. August – 3. September 2010, Addis Ababa
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
WHO Workshop on Assessment of Bioequivalence Data
7 | 31. August – 3. September 2010, Addis Ababa
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.
WHO Workshop on Assessment of Bioequivalence Data
8 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Reference
product
Frequent Deficiencies
Case: manufacturer.
Protocol:
Study report:
WHO Workshop on Assessment of Bioequivalence Data
9 | 31. August – 3. September 2010, Addis Ababa
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…);
WHO Workshop on Assessment of Bioequivalence Data
10 | 31. August – 3. September 2010, Addis Ababa
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.
WHO Workshop on Assessment of Bioequivalence Data
11 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Frequent Deficiencies
WHO Workshop on Assessment of Bioequivalence Data
12 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Frequent Deficiencies
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.
WHO Workshop on Assessment of Bioequivalence Data
13 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Frequent Deficiencies
Identical ECGs for different Volunteers:
WHO Workshop on Assessment of Bioequivalence Data
14 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Frequent Deficiencies
WHO Workshop on Assessment of Bioequivalence Data
15 | 31. August – 3. September 2010, Addis Ababa
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.
WHO Workshop on Assessment of Bioequivalence Data
16 | 31. August – 3. September 2010, Addis Ababa
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).
WHO Workshop on Assessment of Bioequivalence Data
17 | 31. August – 3. September 2010, Addis Ababa
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.
WHO Workshop on Assessment of Bioequivalence Data
18 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Frequent Deficiencies
WHO Workshop on Assessment of Bioequivalence Data
19 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Blood
sampling
Frequent Deficiencies
Case: tmax.
WHO Workshop on Assessment of Bioequivalence Data
20 | 31. August – 3. September 2010, Addis Ababa
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)
WHO Workshop on Assessment of Bioequivalence Data
21 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Frequent Deficiencies
Case: manipulation
WHO Workshop on Assessment of Bioequivalence Data
22 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Frequent Deficiencies
Case: remarkable data
WHO Workshop on Assessment of Bioequivalence Data
23 | 31. August – 3. September 2010, Addis Ababa
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
WHO Workshop on Assessment of Bioequivalence Data
24 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Analytical
method
Frequent Deficiencies
Case: LOQ (2).
WHO Workshop on Assessment of Bioequivalence Data
25 | 31. August – 3. September 2010, Addis Ababa
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.
WHO Workshop on Assessment of Bioequivalence Data
26 | 31. August – 3. September 2010, Addis Ababa
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
WHO Workshop on Assessment of Bioequivalence Data
27 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Frequent Deficiencies
Time period of pre-study validation is identical with
time period of volunteers’ sample analysis
WHO Workshop on Assessment of Bioequivalence Data
28 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Frequent Deficiencies
Bioanalytical part
Critical deviations in % (by 2009)
% critical deviation
Raw data not available
calculation errors
exclusion of QC for P&A
batch acceptance
manual re-integration not
consistent
forged peak
WHO Workshop on Assessment of Bioequivalence Data
29 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Frequent Deficiencies
Bioanalytical part
Major deviations in % (by 2009)
% major deviation
no fresh CC for LT
QC not adequate tu sub
conc
exclusion of QC for P&A
discrepancies
data/report
WHO Workshop on Assessment of Bioequivalence Data
30 | 31. August – 3. September 2010, Addis Ababa
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…
WHO Workshop on Assessment of Bioequivalence Data
31 | 31. August – 3. September 2010, Addis Ababa
GCP/GLP
Frequent Deficiencies
THANK YOU
FOR YOUR ATTENTION
WHO Workshop on Assessment of Bioequivalence Data
32 | 31. August – 3. September 2010, Addis Ababa