**Nomenclature**

**(as excerpted from the Orange Book)**

**Therapeutic Equivalence-Related Terms**

***Pharmaceutical Equivalents***. Drug products are considered
pharmaceutical equivalents if they contain the same active
ingredient(s), are of the same dosage form, route of administration and
are identical in strength or concentration (e.g., chlordiazepoxide
hydrochloride, 5mg capsules). Pharmaceutically equivalent drug products
are formulated to contain the same amount of active ingredient in the
same dosage form and to meet the same or compendial or other applicable
standards (i.e., strength, quality, purity, and identity), but they may
differ in characteristics such as shape, scoring configuration, release
mechanisms, packaging, excipients (including colors, flavors,
preservatives), expiration time, and, within certain limits, labeling.

***Pharmaceutical Alternatives***. Drug products are considered
pharmaceutical alternatives if they contain the same therapeutic moiety,
but are different salts, esters, or complexes of that moiety, or are
different dosage forms or strengths (e.g., tetracycline hydrochloride,
250mg capsules vs. tetracycline phosphate complex, 250mg capsules;
quinidine sulfate, 200mg tablets vs. quinidine sulfate, 200mg capsules).
Data are generally not available for FDA to make the determination of
tablet to capsule bioequivalence. Different dosage forms and strengths
within a product line by a single manufacturer are thus pharmaceutical
alternatives, as are extended-release products when compared with
immediate- or standard-release formulations of the same active
ingredient.

***Therapeutic Equivalents***. Drug products are considered to be
therapeutic equivalents only if they are pharmaceutical equivalents and
if they can be expected to have the same clinical effect and safety
profile when administered to patients under the conditions specified in
the labeling.

FDA classifies as therapeutically equivalent those products that meet
the following general criteria: (1) they are approved as safe and
effective; (2) they are pharmaceutical equivalents in that they
(a) contain identical amounts of the same active drug ingredient in the
same dosage form and route of administration, and (b) meet compendial or
other applicable standards of strength, quality, purity, and identity;
(3) they are bioequivalent in that (a) they do not present a known or
potential bioequivalence problem, and they meet an acceptable *in vitro*
standard, or (b) if they do present such a known or potential problem,
they are shown to meet an appropriate bioequivalence standard; (4) they
are adequately labeled; and (5) they are manufactured in compliance with
Current Good Manufacturing Practice regulations. *The concept of
therapeutic equivalence, as used to develop the List, applies only to
drug products containing the same active ingredient(s) and does not
encompass a comparison of different therapeutic agents used for the same
condition (e.g., propoxyphene hydrochloride vs. pentazocine
hydrochloride for the treatment of pain)*. Any drug product in the List
repackaged and/or distributed by other than the application holder is
considered to be therapeutically equivalent to the application holder\'s
drug product even if the application holder\'s drug product is single
source or coded as non-equivalent (e.g., **BN**). Also, distributors or
repackagers of an application holder\'s drug product are considered to
have the same code as the application holder. Therapeutic equivalence
determinations are not made for unapproved, off-label indications.

FDA considers drug products to be therapeutically equivalent if they
meet the criteria outlined above, even though they may differ in certain
other characteristics such as shape, scoring configuration, release
mechanisms, packaging, excipients (including colors, flavors,
preservatives), expiration date/time and minor aspects of labeling
(e.g., the presence of specific pharmacokinetic information) and storage
conditions. When such differences are important in the care of a
particular patient, it may be appropriate for the prescribing physician
to require that a particular brand be dispensed as a medical necessity.
With this limitation, however, FDA believes that products classified as
therapeutically equivalent can be substituted with the full expectation
that the substituted product will produce the same clinical effect and
safety profile as the prescribed product.

***Bioavailability***. This term means the rate and extent to which the
active ingredient or active moiety is absorbed from a drug product and
becomes available at the site of action. For drug products that are not
intended to be absorbed into the bloodstream, bioavailability may be
assessed by measurements intended to reflect the rate and extent to
which the active ingredient or active moiety becomes available at the
site of action.

***Bioequivalent Drug Products***. This term describes pharmaceutical
equivalent or alternative products that display comparable
bioavailability when studied under similar experimental conditions.
Section 505 (j)(7)(B) of the Act describes one set of conditions under
which a test and reference listed drug shall be considered
bioequivalent:

the rate and extent of absorption of the test drug do not show a
significant difference from the rate and extent of absorption of the
reference drug when administered at the same molar dose of the
therapeutic ingredient under similar experimental conditions in either a
single dose or multiple doses; or

the extent of absorption of the test drug does not show a significant
difference from the extent of absorption of the reference drug when
administered at the same molar dose of the therapeutic ingredient under
similar experimental conditions in either a single dose or multiple
doses and the difference from the reference drug in the rate of
absorption of the drug is intentional, is reflected in its proposed
labeling, is not essential to the attainment of effective body drug
concentrations on chronic use, and is considered medically insignificant
for the drug.

Where these above methods are not applicable (e.g., for drug products
that are not intended to be absorbed into the bloodstream), other *in
vivo* or *in vitro* test methods to demonstrate bioequivalence may be
appropriate.

Bioequivalence may sometimes be demonstrated using an *in vitro*
bioequivalence standard, especially when such an *in vitro* test has
been correlated with human *in vivo* bioavailability data. In other
situations, bioequivalence may sometimes be demonstrated through
comparative clinical trials or pharmacodynamic studies.

**Statistical Criteria for Bioequivalence**

Under the Drug Price Competition and Patent Term Restoration Act of
1984, manufacturers seeking approval to market a generic drug product
must submit data demonstrating that the drug product is bioequivalent to
the pioneer (innovator) drug product. A major premise underlying the
1984 law is that bioequivalent drug products are therapeutically
equivalent and, therefore, interchangeable.

Bioavailability refers to the rate and extent to which the active
ingredient or therapeutic ingredient is absorbed from a drug product and
becomes available at the site of drug action (Federal Food, Drug and
Cosmetic Act, section 505(j)(8)). Bioequivalence refers to equivalent
release of the same drug substance from two or more drug products or
formulations. This leads to an equivalent rate and extent of absorption
from these formulations. Underlying the concept of bioequivalence is the
thesis that, if a drug product contains a drug substance that is
chemically identical and is delivered to the site of action at the same
rate and extent as another drug product, then it is equivalent and can
be substituted for that drug product. Methods used to define
bioequivalence can be found in 21 CFR 320.24, and include (1)
pharmacokinetic (PK) studies, (2) pharmacodynamic (PD) studies, (3)
comparative clinical trials, and (4) in-vitro studies. The choice of
study used is based on the site of action of the drug and the ability of
the study design to compare drug delivered to that site by the two
products.

The standard bioequivalence (PK) study is conducted using a
two-treatment crossover study design in a limited number of volunteers,
usually 24 to 36 adults. Alternately, a four-period, replicate design
crossover study may also be used. Single doses of the test and reference
drug products are administered and blood or plasma levels of the drug
are measured over time. Pharmacokinetic parameters characterizing rate
and extent of drug absorption are evaluated statistically. The PK
parameters of interest are the resulting area under the plasma
concentration-time curve (AUC), calculated to the last measured
concentration (AUC~(0-t)~) and extrapolated to infinity (AUC~(0-inf)~),
for extent of absorption; and the maximum or peak drug concentrations
(Cmax), for rate of absorption. Crossover studies may not be practical
in drugs with a long half-life in the body, and a parallel study design
may be used instead. Alternate study methods, such as in-vitro studies
or equivalence studies with clinical or pharmacodynamic endpoints, are
used for drug products where plasma concentrations are not useful to
determine delivery of the drug substance to the site of activity (such
as inhalers, nasal sprays and topical products applied to the skin).

The statistical methodology for analyzing these bioequivalence studies
is called the two one-sided test procedure. Two situations are tested
with this statistical methodology. The first of the two one-sided tests
determines whether a generic product (test), when substituted for a
brand-name product (reference) is significantly less bioavailable. The
second of the two one-sided tests determines whether a brand-name
product when substituted for a generic product is significantly less
bioavailable. Based on the opinions of FDA medical experts, a difference
of greater than 20% for each of the above tests was determined to be
significant, and therefore, undesirable for all drug products.
Numerically, this is expressed as a limit of test-product
average/reference-product average of 80% for the first statistical test
and a limit of reference-product average/test-product average of 80% for
the second statistical test. By convention, all data is expressed as a
ratio of the average response (AUC and Cmax) for test/reference, so the
limit expressed in the second statistical test is 125% (reciprocal of
80%).

For statistical reasons, all data is log-transformed prior to conducting
statistical testing. In practice, these statistical tests are carried
out using an analysis of variance procedure (ANOVA) and calculating a
90% confidence interval for each pharmacokinetic parameter (Cmax and
AUC). The confidence interval for both pharmacokinetic parameters, AUC
and Cmax, must be entirely within the 80% to 125% boundaries cited
above. Because the mean of the study data lies in the center of the 90%
confidence interval, the mean of the data is usually close to 100% (a
test/reference ratio of 1). Different statistical criteria are sometimes
used when bioequivalence is demonstrated through comparative clinical
trials, pharmacodynamic studies, or comparative in-vitro methodology.

The bioequivalence methodology and criteria described above
simultaneously control for both, differences in the average response
between test and reference, as well as the precision with which the
average response in the population is estimated. This precision depends
on the within-subject (normal volunteer or patient) variability in the
pharmacokinetic parameters (AUC and Cmax) of the two products and on the
number of subjects in the study. The width of the 90% confidence
interval is a reflection in part of the within-subject variability of
the test and reference products in the bioequivalence study. A test
product with no differences in the average response when compared to the
reference might still fail to pass the bioequivalence criteria if the
variability of one or both products is high and the bioequivalence study
has insufficient statistical power (i.e., insufficient number of
subjects). Likewise, a test product with low variability may pass the
bioequivalence criteria, when there are somewhat larger differences in
the average response.

This system of assessing bioequivalence of generic products assures that
these substitutable products do not deviate substantially in in-vivo
performance from the reference product. The Office of Generic Drugs has
conducted two surveys to quantify the differences between generic and
brand name products. The first survey included 224 bioequivalence
studies submitted in approved applications during 1985 and 1986. The
observed average differences between reference and generic products for
AUC was 3.5% (JAMA, Sept. 4, 1987, Vol. 258, No. 9). The second survey
included 127 bioequivalence studies submitted to the agency in 273 ANDAs
approved in 1997. The three measures reviewed include AUC~(0-t),~
AUC~(0-inf)~, and Cmax. The observed average differences between the
reference and generic products were [+]{.underline} 3.47% (SD 2.84) for
AUC~(0-t)~, [+]{.underline} 3.25% (SD 2.97) for AUC~(0-inf)~, and
[+]{.underline} 4.29% (SD 3.72) for Cmax (JAMA, Dec. 1, 1999, Vol. 282,
No. 21).

The primary concern from the regulatory point of view is the protection
of the patient against approval of products that are not bioequivalent.
The current practice of carrying out two one-sided tests at the 0.05
level of significance ensures that there is no more than a 5% chance
that a generic product that is not truly equivalent to the reference
will be approved.