(edited by Jaime_R on 2007-08-17 12:48)
Posting: # 986
A very naive and layman question!
How do one consider the biological variation in determining the bioequivalncy of two formulations? Isnt it possible for two products to fail equivalency test in vivo (due to interindividaul differences) even though their all in vitro paratmeters are identical?
Edit: Category and Subject changed. [Jaime]
Posting: # 987
» How do one consider the biological variation in determining the
» bioequivalncy of two formulations?
By performing an in vivo bioequivalence study.
» Isnt it possible for two products to fail equivalency test in vivo (due
» to interindividaul differences) even though their all in vitro paratmeters
» are identical?
Yes, this is not even possible, but very likely if:
1. the drug belongs to BCS classes II and IV (permeability controls absorption),
2. your drug belongs to BCS I (or maybe III) and your dissolution method is not discriminative,
3. no IVIVC (in vivo - in vitro correlation) exists.
-> 1. For such a drug you will never be able to predict BE, because you are simply missing the important barrier (the gut wall) in the dissolution apparatus. Therefore similarity of in vitro dissolution profiles is meaningless in predicting the in vivo situation.
-> 2. In such a case you will fail to show in vivo BE, because your predictions are wrong.
-> 3. This is just a special case of #2 - you tried hard, but failed.
Since in vivo bioequivalence is a surrogate of clinical efficacy/safety this study is the 'gold standard'.
Some people call volunteers participating in a BE study 'human test tubes' because we are comparing the performance of formulations in a kind of 'biological dissolution model'. Only this model incorporates biological variability. Just remember that we will treat patients with the new formulation - not a dissolution beaker...
Posting: # 989
I am sorry about my ignorance and naivety in this BA/BE area.
Actually my question was not in context of IVIVC but the interindividual variability in response to formulations (pharmacogenomics context!!!!).
Are bioequivalnce studies supposed to be performed in identical population? (ie. same age, sex, race, ethinicity, pathophysiological condition etc)? For known/unknown reasons there may be differences in PK characteristics of formulations in different populations. If so how much variation is allowed to pass the equivalency test?
Posting: # 990
» I am sorry about my ignorance and naivety in this BA/BE area.
You don't have to be sorry; ignorance and naivety should lead to curiosity which is the driving force in science!
» Actually my question was not in context of IVIVC but the interindividual variability in response to formulations (pharmacogenomics context!!!!).
With very few exceptions (long half-life drugs, some studies in patients) BE studies are perfomed in healthy subjects in a cross-over design. Therefore only individual PK responses within subjects are compared - interindividual variability e.g., due to different genotypes) does not count (or to be precise: is separated from the treatment effect in the statistical model). There are many drugs showing very high intersubject variability due to polymorphism, but still low intrasubject variability.
» Are bioequivalnce studies supposed to be performed in identical population? (ie. same age, sex, race, ethinicity, pathophysiological condition etc)?
As said above: generally healthy subjects.
Actual criteria may differ between countries, but quoting
'We recommend that, unless otherwise indicated by a specific guidance, subjects recruited for in vivo BE studies be 18 years of age or older and capable of giving informed consent. This guidance recommends that in vivo BE studies be conducted in individuals representative of the general population, taking into account age, sex, and race. We recommend that if the drug product is intended for use in both sexes, the sponsor attempt to include similar proportions of males and females in the study. If the drug product is to be used predominantly in the elderly, we also recommend that the sponsor attempt to include as many subjects of 60 years of age or older as possible.'
If the drug is subjected to polymorphism, a BE study should be performed in geno-/phenotyped subjects, if:
- a parallel design is used (e.g., for drugs with a long half-life); groups should be stratified for the respective geno-/phenotype. Example: if 20% of the population are slow/poor metabolisers and 80% fast/extensive ones, both groups (treated with either test or reference) should consist of the same percentage of SMs/FMs. Otherwise it would be impossible to calculate the treatment effect properly.
- in a cross-over study, if safety concerns do not allow the inclusion of poor metabolisers (mainly multiple dose studies).
A regulatory example is given by the EU-EMEA (Section 3.2.4 Genetic phenotyping):
'Phenotyping and/or genotyping of subjects should be considered for exploratory bioavailability studies and all studies using parallel group design. It may be considered as well in crossover studies (e.g. bioequivalence, dose proportionality, food interaction studies etc.) for safety or pharmacokinetic reasons. If a drug is known to be subject to major genetic polymorphism, studies could be performed in panels of subjects of known phenotype or genotype for the polymorphism in question.'
» For known/unknown reasons there may be differences in PK characteristics of formulations in different populations. If so how much variation is allowed to pass the equivalency test?
There is no limit on inter-subject variability. Of course there's a difference in plasma concentrations after the same molar dose in a Sumo-wrestler and an anorectic fashion model; but this is not what we are interested in the BE setting.
Edit: FDA-link corrected to latest archived copy. [Helmut]
Posting: # 1326
» If the drug is subjected to polymorphism, a BE study should be performed
» in geno-/phenotyped subjects, if:
» - a parallel design is used (e.g., for drugs with a long half-life);
» groups should be stratified for the respective geno-/phenotype.
» Example: if 20% of the population are slow/poor metabolisers and 80%
» fast/extensive ones, both groups (treated with either test or reference)
» should consist of the same percentage of SMs/FMs. Otherwise it would be
» impossible to calculate the treatment effect properly.
Just a few comments. IMHO it's no good idea to stratify groups for the phenotype, because drop-outs will change the SM (slow metabolizers) / FM (fast metabolizers)-ratio in such a way, that the treatment effect (which is based on group's means) will be biased.
Expanding your example:
Parallel design (2 groups of 30 subjects each; 24 FM (80%) and 6 SM (20%) in each group), responses (FM = 1, SM = 10)
Complete data set: GMT 1.58, GMR 1.58, GMR 100%
1 Drop out (Reference group, SM): GMT 1.58, GMR 1.49, GMR 1.07%
1 Drop out (Reference group, FM): GMT 1.58, GMR 1.61, GMR 0.98%
Therefore IMHO mixed groups should be avoided; only FM should be studied instead.
If stratified groups are to be used (i.e., due to a regulatory requirement), I would suggest laying down a procedure in the SAP excluding a subject of the same phenotype of the repective other group in a predefined blinded manner in order to keep the SM/FM ratio balanced. However, such a method is suboptimal.
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