Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September |1 | Prequalification programme: Priority essential medicines Training Workshop for evaluators from National Medicines Regulatory Authorities in the East African Community: Evaluation of quality and inter-changeability of medicinal products. Dar Es Salaam United Republic of Tanzania 10 – 14 September 2007

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September |2 | Training Workshop on Evaluation of quality and interchangeability of medicinal products. Examples of problems in bioequivalence studies Presenter: Drs. J. Welink Senior pharmacokineticist Medicines Evaluation Board, NL WHO adviser

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September |3 | Bioequivalence * Note to applicants on the choice of comparator products for the prequalification project * Guideline on generics - Annex 7 (Multisource (generic) pharm. products: guidelines on registration requirements to establish interchangeability) - Annex 11 (Guidance on the selection of comparator pharm. products for equivalence assessment of interchangeable multisource (generic) products)

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September |4 | Bioequivalence Same pharmaceutical form; bioequivalence study needed

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September |5 | Bioequivalence Different pharmaceutical form; no registration on bioequivalence only

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September |6 | Bioequivalence Nearly identical; no bioequivalence study needed

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September |7 | Bioequivalence BIOEQUIVALENCE acceptance criteria: comparative rate and extent of absorption: 90% CI for the Test/Reference for C max and AUC within 80 – 125% pharmaceutical equivalence methods: in principle comparative pharmacokinetics; in specific cases pharmacodynamic, clinical or in vitro studies IR tablets and capsules considered the same pharmaceutical form

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September |8 | Bioequivalence ref. BRIDGING STUDIES clinical batchcomm.batchchanged batch scale up variations ref.test approval innovator approval generic acceptance variations innovator generic bioequiv.batchcomm. batchchanged batch test ref.test scale upvariations acceptance variations ref.

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September |9 | Assessment Expression of interest (EOI): HIV/AIDS medication Antimalarial and tuberculosis medicines Reproductive health

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Assessment 2006: appr. 280 expressions of Interest were 34 files for solutions for injection requiring no BE study 222 files for tablets/capsules/oral suspensions requiring BE study 19 submissions for oral solutions about 80 products up to now have been found acceptable …… …… …….

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Assessment

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Assessment

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Assessment Update June 2007: 3 solutions for injections 399 expressions of interest (+ 119) 13 oral solutions 103 tablets/capsules

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Assessment Update June 2007: 75 accepted of the additional 119 submissions 24 additional data requested 5 rejected 12 innovator products

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Assessment Update June 2007: 146 accepted of the total of 399 submissions 29 additional data requested 20 rejected 175 cancelled/withdrawn all prequalified PI are from innovator companies

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | 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

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples GCP/GLP criteria local market ≠ world market GLP fraud original data/documents not available

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Case: reanalysis statistical analysis could not confirm values obtained by applicant GCP/GLP

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | 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

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples subjects Case: Protocol stated that 32 subjects were selected and included in the study.

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | 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

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples subjects Case: Exclusion of subjects (1). Subject 26:

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | 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).

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples subjects Case: Exclusion of subjects (2). subject excluded!

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | 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).

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Food can affect the rate and extent of absorption!! Food effect delay in absorption: increase in absorption: decrease in absorption:

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Food effect Case: Fasting: Fed:

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | 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%

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Case: sampling scheme. Drug: literature reported t max 2 – 7 hours Blood sampling

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Case: sampling period. - AUC 0-t = /- 346; AUC inf = /- 378; t elim. = 3.4 hours; sampling period 8 hours Blood sampling

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Case: t max. Blood sampling

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Reference product Case: manufacturer. Protocol : Study report:

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | 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!

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Reference product Case: change manufacturing process.

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Test product Case: formulation. Application: Studied:

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Case: batch size. Test product

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | 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).

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Case: LOQ (2). Analytical method

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Case: stability (1). Analytical method

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Case: stability (2). Case: stability (3). Analytical method

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Results: Pharmacokinetic data - check PK results; also C-t curves - in line with to be expected - normal variability PK data

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Case: C max. PK data

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Case: C-t curves. PK data

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples -Parent or metabolite? Parent normally to be used as representative for the rate of absorption. metabolite: 90% CI AUC and C max within 80 – 125% but parent..! Statistical analysis Case: analyte.

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | 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

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Examples Case: testing. Statistical analysis

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | 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

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Last example Case: PK variable. - t elim. : 15 h - sampling period 120 hours - parametric testing calculated 90% CI: AUC 0-t 0.96 – 1.26 (n=26) AUC inf 0.98 – 1.23 (n=25) C max 0.92 – 1.23 (n=26) Conclusion applicant: Bioequivalent based upon AUCinf Statistical analysis

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | Last example Case: PK variable. Conclusion assessor: Not bioequivalent! AUC 0-t most reliable for extent of absorption n=25 for AUC inf because for 1 subject AUC inf could not be calculated Statistical analysis

Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / September | End Thank you for your attention