WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September

1. WHO Workshop on Assessment of Bioequivalence Data • Addis Ababa, 31. August – 3. September • Frequent Deficiencies Dr. Henrike Potthast (henrike.potthast@bfarm.de) WHO Workshop on Assessment of Bioequivalence Data, Addis Ababa, 31. August – 3. September 2010

2. Frequent Deficiencies GCP/GLP Inspection of bioequivalence studies Critical and major deviations observed during WHO inspections of CROs by WHO inspectors

3. Frequent Deficiencies GCP/GLP 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.

4. Frequent Deficiencies GCP/GLP 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

5. Frequent Deficiencies GCP/GLP 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 ).

6. Frequent Deficiencies GCP/GLP 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).

7. Frequent Deficiencies GCP/GLP 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

8. 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.

9. Frequent Deficiencies Reference product Case: manufacturer. Protocol: Study report:

10. 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…);

11. Frequent Deficiencies No drug testing was performed on the subjects. Therefore in fact there is no guarantee that the drug abstinence is respected.

12. Frequent Deficiencies

13. 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.

14. Frequent Deficiencies Identical ECGs for different Volunteers:

15. Frequent Deficiencies

16. 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.

17. 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).

18. 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.

19. Frequent Deficiencies

20. Frequent Deficiencies Blood sampling Case: tmax.

21. 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)

22. Frequent Deficiencies Case: manipulation

23. Frequent Deficiencies GCP/GLP Case: remarkable data

24. Frequent Deficiencies Analytical method Case: LOQ (1). • LOQ: 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

25. Frequent Deficiencies Analytical method Case: LOQ (2).

26. 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.

27. 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

28. Frequent Deficiencies Time period of pre-study validation is identical with time period of volunteers’ sample analysis

29. Frequent Deficiencies Bioanalytical partCritical deviations in % (by 2009)

30. Frequent Deficiencies Bioanalytical partMajor deviations in % (by 2009)

31. Frequent Deficiencies Use of correction-fluid and overwriting on CRFs and other raw data. Lack of documentation on monitoring and auditing …and more…

32. Frequent Deficiencies THANK YOU FOR YOUR ATTENTION