Examples of deficiencies in submitted data Drs. J. Welink Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October |2 | GCP overview Bioanalytical part Critical deviations in %

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October |3 | GCP overview Bioanalytical part Major deviations in %

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October |4 | Deficiencies Overall: no bio-study submitted insufficient clinical data Test and Reference product outside the 90% confidence intervals Inadequate validation method of the bioanalysis no submission of dissolution test study design outliers GLP/GCP

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October |5 | Examples Subjects included: - subjects: normal healthy volunteers, male, years * report all demographic data * report all withdrawals from study and reasons why * protocol: handling! Exclusion only when: - subject had vomited shortly after intake of product - analytical problem subjects

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October |6 | Examples subjects Case: Report stated that 32 subjects were selected and included in the study.

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October |7 | Examples subjects Case: Exclusion of subjects (1). - protocol 28 subjects enrolled - PK data 24 subjects used as defined by protocol - two drop-outs (for personal reason) - 26 subjects completed the study - selection procedure replacements not defined!! - replacements subjects 25 and 27

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October |8 | Examples subjects Case: Exclusion of subjects (1). Subject 26:

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October |9 | Examples - number of subjects: 36 - used for statistical analysis: 35 - reason: low drug plasma levels in one subject calculated 90% CI: AUC 0-t 0.83 – 1.07 C max 0.82 – 1.04 Conclusion: Bioequivalent! subjects Case: Exclusion of subjects (2).

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples subjects Case: Exclusion of subjects (2). subject excluded!

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples - number of subjects: 36 - used for statistical analysis: 36 calculated 90% CI: AUC 0-t 0.76 – 1.03 C max 0.79 – 1.02 Conclusion: not bioequivalent! subjects Case: Exclusion of subjects (2).

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Blood sampling Adequate sampling times and period. - reliable estimation of Cmax - reliable estimation of extent of absorption (AUC) AUC 0-t / AUC inf > 80%

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: sampling scheme. Drug: literature reported t max 2 – 7 hours Blood sampling

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Case: t max. Blood sampling

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Elimination half-life

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Reference product Case: manufacturer. Protocol : Study report:

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Reference product Case: change manufacturing process. - normal crossover bioequivalence study - number of subjects 38 - Test: ethionamide 250 mg capsule - Reference: Trecator-SC 250 mg tablet - 90% CI: AUC 0-t 0.95 – 1.28 C max 1.02 – 1.51 Conclusion: Not bioequivalent!

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Reference product Case: change manufacturing process.

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Test product Case: formulation. Application: Studied:

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples - LOQ: 10 ng/ml, sampling period 96 hours - AUC 0-t : 639 +/- 258 ng.h/ml - AUC inf : /- 379 ng.h/ml - C max : 31 +/- 14 ng/ml Analytical method Case: LOQ (1).

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: LOQ (2). Analytical method

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Specificity/selectivity: Analytical method

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: stability (1). Analytical method

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: stability (2). Case: stability (3). Analytical method

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Results: Pharmacokinetic data - check PK results; also C-t curves - in line with to be expected - normal variability PK data

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Case: C max. PK data

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: C-t curves. PK data

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples - number of subjects: 24 - used for statistical analysis: 24 - non-parametric testing - reason: non normal distribution calculated 90% CI: AUC inf 0.98 – 1.23 C max 0.99 – 1.24 Conclusion: Bioequivalent! Case: testing. Statistical analysis

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: testing. Statistical analysis

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: testing. - number of subjects: 24 - used for statistical analysis: 24 - parametric testing !!!!!!!!!! - reason: detection of an outlier considered not acceptable calculated 90% CI: AUC 0-t 0.98 – 1.23 C max 1.01 – 1.38 Conclusion: Not bioequivalent! non parametric testing considered not acceptable! Statistical analysis

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples GCP/GLP criteria local market ≠ world market GLP fraud original data/documents not available

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: reanalysis statistical analysis could not confirm values obtained by applicant GCP/GLP

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: integration GCP/GLP

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: improper documentation GCP/GLP

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: manipulation GCP/GLP

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: manipulation GCP/GLP

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Examples Case: manipulation GCP/GLP

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Example Case: remarkable data GCP/GLP

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Example Case: integration (1) GCP/GLP

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Example Case: integration (2) GCP/GLP

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Example Case: falsified data GCP/GLP

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | Example Case: falsified data GCP/GLP

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October | End Thank you for your attention