CLINICAL SIGNIFICANCE OF BIOEQUIVALENCE STUDIES, BIOEQUIVALENCE, REASONS TO PERFORM BIOEQUIVALENCE STUDIES , NEED FOR BIOEQUIVALENCE STUDIES, IMPORTANCE OF BIOEQUIVALANCE STUDIES, DETERMINATION OF BIOEQUIVALENCE OF A DRUG PRODUCT, CLINICAL SIGNIFICANCE.

1. Presented by
Durgadevi.G
1st M.pharm.
Dept. of pharmaceutical analysis
PSG college of pharmacy.

2.  It is a relative term which denotes that the drug substance in two or more
identical dosage forms, reaches the systemic circulation at the same relative
rate and to the same relative extent i.e. their plasma concentration-time
profiles will be identical without significant statistical differences.
 When statistically significant differences are observed in the bioavailability
of two or more drug products, bio- inequivalence is indicated.
 The absence of a significant difference in the rate and extent to which the
active ingredient or active moiety in pharmaceutical equivalents or
pharmaceutical alternatives becomes available at the site of drug action
when administered at the same molar dose under similar conditions in an
appropriately designed study.

3.  To enable clinical trial formulations to be modified or production ‘scaled up’
throughout a drug’s development.
 To compare a clinical trial formulation with the ‘to be marketed’ product
just prior to filing
 To compare a generic drug product with a corresponding reference drug.
 To change the dosage regimen by means of a change in formulation
 Immediate release
 Modified-release

4.  New product is intended to be a substitute for an approved medicinal
product as a pharmaceutical equivalent or alternative
 To ensure clinical performance of such drug products
 Bioequivalence studies are conducted if there is:
 A risk of bio-in equivalence and/or
 A risk of pharmacotherapeutics failure or diminished clinical safety
 In vivo bioavailability / bioequivalence studies and in vitro dissolution
testing recommended to applicants intending to submit Investigational new
drug application (INDs)New drug applications (NDAs)Abbreviated new
drug applications (ANDAs) for conventional and extended release dosage
forms administered orally.
 In conditions where a suitable method for determining active drug is not
available, an indirect indication of bioavailability and bioequivalence by
comparing the pharmacodynamic responses of the formulations may be
possible

5.  To evaluate the absolute bioavailability of dosage form compared with
reference dosage forms.
 Dose proportionality study to determine if bioavailability parameters are
linear over proposed dosage range.
 Intra/inter subject variability
 Intervention study to examine effect of e.g. Food and concomitant
medication.
 Dosage form proportionality study to determine if equipotent drug
treatments administered at different dose strength of the market form
produce equivalent drug bioavailability.
 Bioequivalence study needed as a result of changes in the formulation or
manufacturing processes.

6. Different approaches for determination of bioequivalence of a drug product are:
 An in vivo test in humans in which the concentration of the active ingredient and
when appropriate, its active metabolites, in blood, plasma, serum or other suitable
biological fluid is measured as a function of time.
 An in vivo test in humans in which the urinary excretion of the active ingredient and
when appropriate, its active metabolites are measured as a function of time.
 An in vitro test that has been correlated with and is predictive of human
bioavailability profile or the one acceptable to FDA (e.g. dissolution rate test) that
ensures human in vivo bioavailability.
 An in vivo test in humans in which an appropriate pharmacological effect of the
active ingredient and when appropriate, its active metabolites are measured as a
function of time if this effect can be measured with adequate accuracy, sensitivity
and reproducibility
 Well-controlled clinical trials that establish the efficacy and safety of the drug
product, for purpose of determining bioavailability, or comparative clinical trials, for
purpose of demonstrating bioequivalence.

8. Products requiring be studies are mainly
(1) drugs with narrow margin of safety,
e.g. digoxin, antiarrhythmics, anticoagulants, cytostatics, lithium, phenytoin,
cyclosporine, sulphonylureas, theo-phylline
(2) critical use drugs, i.e. drugs indicated for serious conditions requiring
assured therapeutic response,
e.g. antiinfectives, cardiovascular drugs, antiepileptics, antiasthmatics; and
(3) sustained or modified release products, due to the difficult formulation.

9.  In practice, bioequivalence in drug absorption has been interpreted that the
confidence interval for the ratio of means (of drug absorption) is within
bioequivalence limits.
 An alternative would be to show that the tolerance intervals (or a
distribution free model) overlap sufficiently.
 Many practitioners interpret that generic drug products and the innovative
drug product can be used interchangeably because they are therapeutically
equivalent.
 The FDA, however, does not indicate that approved generic drug products
and the innovative drug products can be used interchangeably.
 The FDA only indicates that an approved generic drug product can be used
as a substitute to the innovative drug product.
 Basically, drug interchangeability can be classified either as
 drug prescribability or
 drug switchability

10.  Drug prescribability is defined as the physician’s choice for prescribing an
appropriate drug product for his/her new patients between a brand-name
drug product and a number of generic drug products that have been shown
to be bioequivalent to the brand-name drug product.
 Drug switchability, on the other hand, is related to the switch from a drug
product (e.g., a brand-name drug product) to an alternative drug product
(e.g., a generic copy of the brand-name drug product) within the same
subject, whose concentration of the drug product has been titrated to a
steady, efficacious, and safe level.
 As a result, drug switchability is considered more critical than drug
prescribability in the study of drug interchangeability for patients who have
been on medication for a while.
 Drug switchability, therefore, is exchangeability within the same subject.

11. Bioequivalence (BE) study is required to show whether a generic copy product
can be interchangeable with the brand innovator product.
E.g.: BE studies of clopidogrel generics :
 Clopidogrel is a prodrug that must undergo hepatic metabolism to become
the active metabolite.
 The active metabolite is highly unstable and thus difficult to measure.
 Therefore, the BE study of clopidogrel may be a pharmacokinetic study or a
pharmacodynamic study.
 The pharmacokinetic BE study of clopidogrel is based on the measurement
of clopidogrel parent compound
 The pharmacodynamic BE study of clopidogrel is based on the inhibition of
ADP binding to its platelet membrane receptors, P2Y12, which causes
platelet aggregation.

12.  Bioequivalence for most of oral tablets or capsules is demonstrated in vivo
by comparing the rate and extent of absorption that is bioavailability of the
generic product with that of the innovator product.
 This is done by measuring the active ingredient concentration in blood,
plasma, serum or other biological fluids over a certain period of time for
both the generic and innovator products, also called test and reference drugs
respectively.
 By doing so the bioequivalence studies frequently rely on pharmacokinetic
measures such as area under the concentration-time curve (AUC) and peak
drug concentration (Cmax)
 Use of Alternate routes:Drugs with high hepatic first pass metabolism
should be given by routes other than oral. ie., sublingual, transdermal eg.,
Nitroglycerine
 High oral doses: Some drugs have high hepatic extraction ratio.
 Less dose in hepatic Disease: In severe hepatic cirrhosis/ portal systemic
shunts, the dose of the drugs with large extraction ration and hepatic first
pass effect should be reduced otherwise toxicity

13.  Bioequivalence studies are very important for the development of a
pharmaceutical preparation in the pharmaceutical industry.
 Their rationale is the monitoring of pharmacokinetic and pharmacodynamic
parameters after the administration of tested drugs.
 The target of such study is to evaluate the therapeutic compatibility of tested
drugs (pharmaceutical equivalents or pharmaceutical alternatives).

14.  Clinical interpretation is important in evaluating the results of a
bioequivalence study.
 Bioequivalence studies should be conducted for the comparison of two
medicinal products containing the same active substance.
 Two products marketed by different licensees, containing same active
ingredient(s), must be shown to be therapeutically equivalent to one another
in order to be considered interchangeable.
 Differences of less than 20% in AUC & Cmax between drug products are
unlikely to be clinically significant in patients.
 Minimize product to product variability by different manufactures & lot to
lot variability with a single manufacture.