Transcript Prequalification programme: Priority essential medicines Training Workshop for evaluators from National

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
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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
E-mail: [email protected]
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Bioequivalence
http://mednet3.who.int/prequal/
* 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)
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Bioequivalence
Same pharmaceutical form;
bioequivalence study needed
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Bioequivalence
Different pharmaceutical form;
no registration on bioequivalence only
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Bioequivalence
Nearly identical;
no bioequivalence study needed
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Bioequivalence
BIOEQUIVALENCE
pharmaceutical equivalence
methods: in principle comparative pharmacokinetics; in specific
cases pharmacodynamic, clinical or in vitro studies
acceptance criteria: comparative rate and extent of absorption:
90% CI for the Test/Reference for Cmax and AUC within 80 – 125%
IR tablets and capsules considered the same pharmaceutical form
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Bioequivalence
BRIDGING STUDIES
variations
scale up
innovator
clinical batch
comm.batch
ref.
test
changed batch
ref.
test
acceptance
variations
approval
innovator
approval
generic
generic
test
ref.
acceptance
variations
test
bioequiv.batch
ref.
test
comm. batch
scale up
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changed batch
variations
Assessment
Expression of interest (EOI):
HIV/AIDS medication
Antimalarial and tuberculosis medicines
Reproductive health
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Assessment
2006: appr. 280 expressions of Interest were
……
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…….
……
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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
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Assessment
Distribution of submissions
Antibacterials
Antimycotics
Antiprotozoals
18
18
other Antivirals
56
Anticancer
34
Nuclosid RTI
24
7
18
86
10
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NRTI Combi
Non-Nucleosid RTI
Prot.I
Assessment
Distribution of prequalifiedAntibacterials
Antimycotics
products (appr. 80)
Antiprotozoals
other Antivirals
8
10
Anticancer
6
Nucleosid RTI
5
2
4
4
2
NRTI Combi
Non-Nucleosid
RTI
Prot.I
32
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Assessment
Update June 2007:
399 expressions of interest (+ 119)
3 solutions for injections
13 oral solutions
103 tablets/capsules
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Assessment
Update June 2007:
of the additional 119 submissions
75 accepted
24 additional data requested
5 rejected
12 innovator products
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Assessment
Update June 2007:
of the total of 399 submissions
146 accepted
29 additional data requested
20 rejected
175 cancelled/withdrawn
all prequalified PI are from innovator companies
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Deficiencies
Overall:
GLP/GCP
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
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Examples
GCP/GLP
 criteria local market ≠ world market
 GLP
 fraud
original data/documents not available
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Examples
GCP/GLP
Case: reanalysis statistical analysis
could not confirm values obtained by
applicant
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Examples
subjects
Subjects included:
- subjects: normal healthy volunteers, male, 18-55 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
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Examples
subjects
Case: Protocol stated that 32 subjects were selected and
included in the study.
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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
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Examples
subjects
Case: Exclusion of subjects (1).
Subject 26:
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Examples
subjects
Case: Exclusion of subjects (2).
- number of subjects: 36
- used for statistical analysis: 35
- reason: low drug plasma levels in one subject
calculated 90% CI:
AUC0-t 0.83 – 1.07
Cmax
Conclusion: Bioequivalent!
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0.82 – 1.04
Examples
subjects
Case: Exclusion of subjects (2).
subject excluded!
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Examples
subjects
Case: Exclusion of subjects (2).
- number of subjects: 36
- used for statistical analysis: 36
calculated 90% CI:
AUC0-t 0.76 – 1.03
Cmax
Conclusion: not bioequivalent!
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0.79 – 1.02
Examples
Food effect
Food can affect the rate and extent of
absorption!!
decrease in absorption:
delay in absorption:
Plasma Conc. mg/L
Plasma Conc. mg/L
Plasma Conc. mg/L
increase in absorption:
Time (h)
Time (h)
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Time (h)
Examples
Food effect
Case:
Fasting:
Fed:
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Examples
Blood
sampling
Adequate sampling times and period.
- reliable estimation of Cmax
- reliable estimation of extent of absorption (AUC)
AUC0-t / AUCinf > 80%
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Examples
Blood
sampling
Case: sampling scheme.
Drug: literature reported tmax 2 – 7 hours
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Examples
Blood
sampling
Case: sampling period.
- AUC0-t = 1600 +/- 346; AUCinf = 1989 +/- 378; telim. = 3.4 hours;
sampling period 8 hours
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Examples
Blood
sampling
Case: tmax.
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Examples
Reference
product
Case: manufacturer.
Protocol:
Study report:
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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:
AUC0-t
0.95 – 1.28
Cmax
1.02 – 1.51
Conclusion: Not bioequivalent!
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Examples
Reference
product
Case: change manufacturing process.
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Examples
Test
product
Case: formulation.
Application:
Studied:
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Examples
Test
product
Case: batch size.
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Examples
Analytical
method
- LOQ:
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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Examples
Analytical
method
Case: LOQ (2).
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Examples
Analytical
method
Case: stability (1).
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Examples
Analytical
method
Case: stability (2).
Case: stability (3).
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Examples
PK data
Results: Pharmacokinetic data
- check PK results; also C-t curves
- in line with to be expected
- normal variability
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Examples
PK data
Case: Cmax.
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Examples
PK data
Case: C-t curves.
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Examples
Statistical
analysis
Case: analyte.
-Parent or metabolite? Parent normally to be used as
representative for the rate of absorption.
metabolite: 90% CI AUC and Cmax within 80 – 125%
but parent..!
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Examples
Statistical
analysis
Case: testing.
- number of subjects: 24
- used for statistical analysis: 24
- non-parametric testing
- reason: non normal distribution
calculated 90% CI: AUCinf 0.98 – 1.23
Cmax
0.99 – 1.24
Conclusion: Bioequivalent!
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Examples
Statistical
analysis
Case: testing.
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Examples
Statistical
analysis
Case: testing.
- number of subjects: 24
- used for statistical analysis: 24
- parametric testing !!!!!!!!!!
- reason: detection of an outlier considered not acceptable
calculated 90% CI:
AUC0-t
Cmax
0.98 – 1.23
1.01 – 1.38
Conclusion: Not bioequivalent!
non parametric testing considered not
acceptable!
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Last example
Statistical
analysis
Case: PK variable.
- telim.: 15 h
- sampling period 120 hours
- parametric testing
calculated 90% CI: AUC0-t 0.96 – 1.26 (n=26)
AUCinf 0.98 – 1.23 (n=25)
Cmax 0.92 – 1.23 (n=26)
Conclusion applicant:
Bioequivalent based upon AUCinf
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Last example
Statistical
analysis
Case: PK variable.
Conclusion assessor: Not bioequivalent!
AUC0-t most reliable for extent of
absorption
n=25 for AUCinf because for 1 subject
AUCinf could not be calculated
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End
Thank you for your attention
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