(as excerpted from the
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 +
3.47% (SD 2.84) for AUC(0-t), + 3.25% (SD 2.97) for AUC(0-inf),
and + 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.