Two medicinal products are bioequivalents if they are
pharmaceutical equivalents or alternatives and if their
bioavailabilities (rate and extent) after administration
in the same molar dose are similar to such degree that
their effects, with respect to both efficacy and
safety, will be essential the same.
• Using bioequivalence as the basis was established by the
“Drug Price Competition and Patent Term Restoration Act of
1984,” also known as the Waxman-Hatch Act.
• This Act permits FDA to approve applications to market
generic versions of brand-name drugs without conducting
costly and duplicative clinical trials.
• At the same time, the brand-name companies can apply for
up to five additional years longer patent protection for the
new medicines they developed.
• Brand-name drugs are subject to the same bioequivalence
tests as generics upon reformulation.
Goals of BE
on changes to
the market is
Establish that a new formulation has
therapeutic equivalence in the rate and
extent of absorption to the reference
Important for linking the commercial drug
product to clinical trial material at time of
Important for post-approval changes in
the marketed drug formulation.
• Contain the same amount of the same active substance in the
same dosage form.
• Meet the same or comparable standards.
• Intended to be administered by the same route.
Pharmaceutical equivalence by itself does not
necessarily imply therapeutic equivalence
Drug particle size, ..
Site of manufacture
Batch size ….
= Therapeutic Equivalence
(Note: Generally, same dissolution specifications)
identical therapeutic moiety, or its precursor not
necessarily the same:
• salt or ester of the therapeutic moiety
• dosage form
• Pharmaceutically equivalent
• Their effects, with respect to both
efficacy and safety, will be
essentially the same as derived
from appropriate studies
If a product is demonstrated to be
therapeutically equivalent to a reference
product, then the products are considered
Concept of interchangeability includes the
equivalence of the dosage form as well as for the
indications and instructions for use.
Therapeutic equivalence of a multiscource
product can be assured when the multiscource
product is both pharmaceutically
equivalent/alternative and bioequivalent.
TE = PE + BE
• AUC: area under the concentration-time curve measure of the
extent of bioavailability
• Cmax: the observed maximum concentration of drug measure of
both the rate of absorption and the extent of bioavailability (µg/mL or
• Tmax: the time after administration of drug at which Cmax is observed
measure of the rate of absorption (minutes or hours)
Note that bioequivalence standards are applied to the pharmacokinetic parameters
AUC and Cmax but not to Tmax.
• Pharmacokinetic Studies
– Area under the concentration-
– Maximum concentration
– A difference of greater than 20%
in Cmax or the AUC represents a
significant difference between the
test and reference compounds
– Time to maximum concentration
To establish BE:
The calculated 90% CI for Cmax & AUC, should fall within range:
80-125% (Range of Bioequivalence)
Non-parametric data 90% CI for Tmax should lie within
clinical acceptable range
Concept of “Half Life”
½ life = how much time it takes for blood levels of drug to decrease
to half of what it was at equilibrium
There are really two kinds of ½ life…
“distribution” ½ life = when plasma levels fall to half what they
were at equilibrium due to distribution to/storage in body’s
“elimination” ½ life = when plasma levels fall to half what they
were at equilibrium due to drug being metabolized and
It is usually the elimination ½ life that is used to determine dosing
schedules, to decide when it is safe to put patients on a new drug