I (4–1–09 Edition)
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Food and Drug Administration, HHS § 320.21
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§ 320.22 21 CFR Ch. I (4–1–09 Edition)
(2) The application agrees to submit, tive July 15, 2009. For the convenience of the
within the time specified by FDA, ei- user, the revised text is set forth as follows:
ther: § 320.21 Requirements for submission of bio-
(i) Evidence measuring the in vivo availability and bioequivalence data.
bioavailability and demonstrating the
in vivo bioequivalence of the drug * * * * *
product that is the subject of the appli-
cation; or (b) * * *
(1) Evidence demonstrating that the drug
(ii) Information to permit FDA to product that is the subject of the abbre-
waive measurement of in vivo bio- viated new drug application is bioequivalent
availability. to the reference listed drug (defined in
(e) Evidence measuring the in vivo § 314.3(b) of this chapter). A complete study
bioavailability and demonstrating the report must be submitted for the bioequiva-
in vivo bioequivalence of a drug prod- lence study upon which the applicant relies
uct shall be obtained using one of the for approval. For all other bioequivalence
studies conducted on the same drug product
approaches for determining bio-
formulation, the applicant must submit ei-
availability set forth in § 320.24. ther a complete or summary report. If a
(f) Information to permit FDA to summary report of a bioequivalence study is
waive the submission of evidence meas- submitted and FDA determines that there
uring the in vivo bioavailability or may be bioequivalence issues or concerns
demonstrating the in vivo bioequiva- with the product, FDA may require that the
lence shall meet the criteria set forth applicant submit a complete report of the
in § 320.22. bioequivalence study to FDA; or
(g) Any person holding an approved
full or abbreviated new drug applica- * * * * *
tion shall submit to FDA a supple-
mental application containing new evi- § 320.22 Criteria for waiver of evidence
of in vivo bioavailability or bio-
dence measuring the in vivo bio- equivalence.
availability or demonstrating the in
vivo bioequivalence of the drug product (a) Any person submitting a full or
that is the subject of the application if abbreviated new drug application, or a
notified by FDA that: supplemental application proposing
(1) There are data demonstrating any of the changes set forth in
that the dosage regimen in the labeling § 320.21(c), may request FDA to waive
is based on incorrect assumptions or the requirement for the submission of
facts regarding the pharmacokinetics evidence measuring the in vivo bio-
of the drug product and that following availability or demonstrating the in
this dosage regimen could potentially vivo bioequivalence of the drug product
result in subtherapeutic or toxic levels; that is the subject of the application.
or An applicant shall submit a request for
(2) There are data measuring signifi- waiver with the application. Except as
cant intra-batch and batch-to-batch provided in paragraph (f) of this sec-
variability, e.g., plus or minus 25 per- tion, FDA shall waive the requirement
cent, in the bioavailability of the drug for the submission of evidence of in
product. vivo bioavailability or bioequivalence
if the drug product meets any of the
(h) The requirements of this section
provisions of paragraphs (b), (c), (d), or
regarding the submission of evidence
(e) of this section.
measuring the in vivo bioavailability
(b) For certain drug products, the in
or demonstrating the in vivo bio-
vivo bioavailability or bioequivalence
equivalence apply only to a full or ab-
of the drug product may be self-evi-
breviated new drug application or a
dent. FDA shall waive the requirement
supplemental application for a finished
for the submission of evidence obtained
dosage formulation.
in vivo measuring the bioavailability
[57 FR 17998, Apr. 28, 1992, as amended at 67 or demonstrating the bioequivalence of
FR 77672, Dec. 19, 2002] these drug products. A drug product’s
EFFECTIVE DATE NOTE: At 74 FR 2862, Jan. in vivo bioavailability or bioequiva-
16, 2009, § 320.21 was amended by revising the lence may be considered self-evident
section heading and paragraph (b)(1), effec- based on other data in the application
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Food and Drug Administration, HHS § 320.22
if the product meets one of the fol- forth in § 320.33, included the drug prod-
lowing criteria: uct in the Approved Drug Products
(1) The drug product: with Therapeutic Equivalence Evalua-
(i) Is a parenteral solution intended tions List, and rated the drug product
solely for administration by injection, as having a known or potential bio-
or an ophthalmic or otic solution; and equivalence problem. A drug product so
(ii) Contains the same active and in- rated reflects a determination by FDA
active ingredients in the same con- that an in vivo bioequivalence study is
centration as a drug product that is the required.
subject of an approved full new drug (d) For certain drug products, bio-
application or abbreviated new drug availability may be measured or bio-
application. equivalence may be demonstrated by
(2) The drug product: evidence obtained in vitro in lieu of in
(i) Is administered by inhalation as a vivo data. FDA shall waive the require-
gas, e.g., a medicinal or an inhalation ment for the submission of evidence
anesthetic; and obtained in vivo measuring the bio-
(ii) Contains an active ingredient in availability or demonstrating the bio-
the same dosage form as a drug product equivalence of the drug product if the
that is the subject of an approved full drug product meets one of the fol-
new drug application or abbreviated lowing criteria:
new drug application. (1) [Reserved]
(3) The drug product: (2) The drug product is in the same
(i) Is a solution for application to the dosage form, but in a different
skin, an oral solution, elixir, syrup, strength, and is proportionally similar
tincture, a solution for aerosolization in its active and inactive ingredients to
or nebulization, a nasal solution, or another drug product for which the
similar other solubilized form; and same manufacturer has obtained ap-
(ii) Contains an active drug ingre- proval and the conditions in para-
dient in the same concentration and graphs (d)(2)(i) through (d)(2)(iii) of
dosage form as a drug product that is this section are met:
the subject of an approved full new
(i) The bioavailability of this other
drug application or abbreviated new
drug product has been measured;
drug application; and
(ii) Both drug products meet an ap-
(iii) Contains no inactive ingredient
propriate in vitro test approved by
or other change in formulation from
FDA; and
the drug product that is the subject of
the approved full new drug application (iii) The applicant submits evidence
or abbreviated new drug application showing that both drug products are
that may significantly affect absorp- proportionally similar in their active
tion of the active drug ingredient or and inactive ingredients.
active moiety for products that are (iv) Paragraph (d) of this section does
systemically absorbed, or that may sig- not apply to delayed release or ex-
nificantly affect systemic or local tended release products.
availability for products intended to (3) The drug product is, on the basis
act locally. of scientific evidence submitted in the
(c) FDA shall waive the requirement application, shown to meet an in vitro
for the submission of evidence meas- test that has been correlated with in
uring the in vivo bioavailability or vivo data.
demonstrating the in vivo bioequiva- (4) The drug product is a reformu-
lence of a solid oral dosage form (other lated product that is identical, except
than a delayed release or extended re- for a different color, flavor, or preserv-
lease dosage form) of a drug product ative that could not affect the bio-
determined to be effective for at least availability of the reformulated prod-
one indication in a Drug Efficacy uct, to another drug product for which
Study Implementation notice or which the same manufacturer has obtained
is identical, related, or similar to such approval and the following conditions
a drug product under § 310.6 of this are met:
chapter unless FDA has evaluated the (i) The bioavailability of the other
drug product under the criteria set product has been measured; and
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§ 320.23 21 CFR Ch. I (4–1–09 Edition)
(ii) Both drug products meet an ap- use, and is considered medically insig-
propriate in vitro test approved by nificant for the drug product.
FDA. (b) Two drug products will be consid-
(e) FDA, for good cause, may waive a ered bioequivalent drug products if
requirement for the submission of evi- they are pharmaceutical equivalents or
dence of in vivo bioavailability or bio- pharmaceutical alternatives whose
equivalence if waiver is compatible rate and extent of absorption do not
with the protection of the public show a significant difference when ad-
health. For full new drug applications, ministered at the same molar dose of
FDA may defer a requirement for the the active moiety under similar experi-
submission of evidence of in vivo bio- mental conditions, either single dose or
availability if deferral is compatible multiple dose. Some pharmaceutical
with the protection of the public equivalents or pharmaceutical alter-
health. natives may be equivalent in the ex-
(f) FDA, for good cause, may require tent of their absorption but not in
evidence of in vivo bioavailability or their rate of absorption and yet may be
bioequivalence for any drug product if considered bioequivalent because such
the agency determines that any dif- differences in the rate of absorption are
ference between the drug product and a intentional and are reflected in the la-
listed drug may affect the bio- beling, are not essential to the attain-
availability or bioequivalence of the ment of effective body drug concentra-
drug product. tions on chronic use, and are consid-
[57 FR 17998, Apr. 28, 1992, as amended at 67 ered medically insignificant for the
FR 77673, Dec. 19, 2002] particular drug product studied.
§ 320.23 Basis for measuring in vivo [57 FR 17999, Apr. 28, 1992, as amended at 67
bioavailability or demonstrating FR 77673, Dec. 19, 2002]
bioequivalence.
(a)(1) The in vivo bioavailability of a § 320.24 Types of evidence to measure
bioavailability or establish bio-
drug product is measured if the prod- equivalence.
uct’s rate and extent of absorption, as
determined by comparison of measured (a) Bioavailability may be measured
parameters, e.g., concentration of the or bioequivalence may be dem-
active drug ingredient in the blood, onstrated by several in vivo and in
urinary excretion rates, or pharma- vitro methods. FDA may require in
cological effects, do not indicate a sig- vivo or in vitro testing, or both, to
nificant difference from the reference measure the bioavailability of a drug
material’s rate and extent of absorp- product or establish the bioequivalence
tion. For drug products that are not in- of specific drug products. Information
tended to be absorbed into the blood- on bioequivalence requirements for
stream, bioavailability may be as- specific products is included in the cur-
sessed by measurements intended to re- rent edition of FDA’s publication ‘‘Ap-
flect the rate and extent to which the proved Drug Products with Thera-
active ingredient or active moiety be- peutic Equivalence Evaluations’’ and
comes available at the site of action. any current supplement to the publica-
(2) Statistical techniques used shall tion. The selection of the method used
be of sufficient sensitivity to detect to meet an in vivo or in vitro testing
differences in rate and extent of ab- requirement depends upon the purpose
sorption that are not attributable to of the study, the analytical methods
subject variability. available, and the nature of the drug
(3) A drug product that differs from product. Applicants shall conduct bio-
the reference material in its rate of ab- availability and bioequivalence testing
sorption, but not in its extent of ab- using the most accurate, sensitive, and
sorption, may be considered to be bio- reproducible approach available among
available if the difference in the rate of those set forth in paragraph (b) of this
absorption is intentional, is appro- section. The method used must be ca-
priately reflected in the labeling, is not pable of measuring bioavailability or
essential to the attainment of effective establishing bioequivalence, as appro-
body drug concentrations on chronic priate, for the product being tested.
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Food and Drug Administration, HHS § 320.24
(b) The following in vivo and in vitro to the bloodstream for systemic dis-
approaches, in descending order of ac- tribution.
curacy, sensitivity, and reproduc- (4) Well-controlled clinical trials that
ibility, are acceptable for determining establish the safety and effectiveness
the bioavailability or bioequivalence of of the drug product, for purposes of
a drug product. measuring bioavailability, or appro-
(1)(i) An in vivo test in humans in priately designed comparative clinical
which the concentration of the active trials, for purposes of demonstrating
ingredient or active moiety, and, when bioequivalence. This approach is the
appropriate, its active metabolite(s), in least accurate, sensitive, and reproduc-
whole blood, plasma, serum, or other ible of the general approaches for
appropriate biological fluid is meas- measuring bioavailability or dem-
ured as a function of time. This ap- onstrating bioequivalence. For dosage
proach is particularly applicable to forms intended to deliver the active
dosage forms intended to deliver the moiety to the bloodstream for systemic
active moiety to the bloodstream for distribution, this approach may be con-
systemic distribution within the body; sidered acceptable only when analyt-
or ical methods cannot be developed to
(ii) An in vitro test that has been permit use of one of the approaches
correlated with and is predictive of outlined in paragraphs (b)(1)(i) and
human in vivo bioavailability data; or (b)(2) of this section, when the ap-
(2) An in vivo test in humans in proaches described in paragraphs
which the urinary excretion of the ac- (b)(1)(ii), (b)(1)(iii), and (b)(3) of this
tive moiety, and, when appropriate, its section are not available. This ap-
active metabolite(s), are measured as a proach may also be considered suffi-
function of time. The intervals at ciently accurate for measuring bio-
which measurements are taken should availability or demonstrating bio-
ordinarily be as short as possible so equivalence of dosage forms intended
that the measure of the rate of elimi- to deliver the active moiety locally,
nation is as accurate as possible. De- e.g., topical preparations for the skin,
pending on the nature of the drug prod- eye, and mucous membranes; oral dos-
uct, this approach may be applicable to age forms not intended to be absorbed,
the category of dosage forms described e.g., an antacid or radiopaque medium;
in paragraph (b)(1)(i) of this section. and bronchodilators administered by
This method is not appropriate where inhalation if the onset and duration of
urinary excretion is not a significant pharmacological activity are defined.
mechanism of elimination. (5) A currently available in vitro test
(3) An in vivo test in humans in acceptable to FDA (usually a dissolu-
which an appropriate acute pharma- tion rate test) that ensures human in
cological effect of the active moiety, vivo bioavailability.
and, when appropriate, its active me- (6) Any other approach deemed ade-
tabolite(s), are measured as a function quate by FDA to measure bio-
of time if such effect can be measured availability or establish bioequiva-
with sufficient accuracy, sensitivity, lence.
and reproducibility. This approach is (c) FDA may, notwithstanding prior
applicable to the category of dosage requirements for measuring bio-
forms described in paragraph (b)(1)(i) of availability or establishing bioequiva-
this section only when appropriate lence, require in vivo testing in hu-
methods are not available for measure- mans of a product at any time if the
ment of the concentration of the moi- agency has evidence that the product:
ety, and, when appropriate, its active (1) May not produce therapeutic ef-
metabolite(s), in biological fluids or ex- fects comparable to a pharmaceutical
cretory products but a method is avail- equivalent or alternative with which it
able for the measurement of an appro- is intended to be used interchangeably;
priate acute pharmacological effect. (2) May not be bioequivalent to a
This approach may be particularly ap- pharmaceutical equivalent or alter-
plicable to dosage forms that are not native with which it is intended to be
intended to deliver the active moiety used interchangeably; or
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§ 320.25 21 CFR Ch. I (4–1–09 Edition)
(3) Has greater than anticipated po- dient or the therapeutic moiety needs
tential toxicity related to pharmaco- to be established after single-dose ad-
kinetic or other characteristics. ministration and in certain instances
[57 FR 17999, Apr. 28, 1992; 57 FR 29354, July
after multiple-dose administration.
1, 1992, as amended at 67 FR 77673, Dec. 19, This characterization is a necessary
2002] part of the investigation of the drug to
support drug labeling.
§ 320.25 Guidelines for the conduct of (2) The reference material in such a
an in vivo bioavailability study. bioavailability study should be a solu-
(a) Guiding principles. (1) The basic tion or suspension containing the same
principle in an in vivo bioavailability quantity of the active drug ingredient
study is that no unnecessary human re- or therapeutic moiety as the formula-
search should be done. tion proposed for marketing.
(2) An in vivo bioavailability study is (3) The reference material should be
generally done in a normal adult popu- administered by the same route as the
lation under standardized conditions. formulation proposed for marketing
In some situations, an in vivo bio- unless an alternative or additional
availability study in humans may pref- route is necessary to answer the sci-
erably and more properly be done in entific question under study. For ex-
suitable patients. Critically ill patients ample, in the case of an active drug in-
shall not be included in an in vivo bio- gredient or therapeutic moiety that is
availability study unless the attending poorly absorbed after oral administra-
physician determines that there is a tion, it may be necessary to compare
potential benefit to the patient. the oral dosage form proposed for mar-
(b) Basic design. The basic design of keting with the active drug ingredient
an in vivo bioavailability study is de- or therapeutic moiety administered in
termined by the following: solution both orally and intravenously.
(1) The scientific questions to be an- (e) New formulations of active drug in-
swered. gredients or therapeutic moieties approved
(2) The nature of the reference mate- for marketing. (1) An in vivo bio-
rial and the dosage form to be tested. availability study involving a drug
(3) The availability of analytical product that is a new dosage form, or a
methods. new salt or ester of an active drug in-
(4) Benefit-risk considerations in re- gredient or therapeutic moiety that
gard to testing in humans. has been approved for marketing can
(c) Comparison to a reference material. be used to:
In vivo bioavailability testing of a drug (i) Measure the bioavailability of the
product shall be in comparison to an new formulation, new dosage form, or
appropriate reference material unless new salt or ester relative to an appro-
some other approach is more appro- priate reference material; and
priate for valid scientific reasons. (ii) Define the pharmacokinetic pa-
(d) Previously unmarketed active drug rameters of the new formulation, new
ingredients or therapeutic moieties. (1) An dosage form, or new salt or ester to es-
in vivo bioavailability study involving tablish dosage recommendation.
a drug product containing an active (2) The selection of the reference ma-
drug ingredient or therapeutic moiety terial(s) in such a bioavailability study
that has not been approved for mar- depends upon the scientific questions
keting can be used to measure the fol- to be answered, the data needed to es-
lowing pharmacokinetic data: tablish comparability to a currently
(i) The bioavailability of the formu- marketed drug product, and the data
lation proposed for marketing; and needed to establish dosage rec-
(ii) The essential pharmacokinetic ommendations.
characteristics of the active drug in- (3) The reference material should be
gredient or therapeutic moiety, such as taken from a current batch of a drug
the rate of absorption, the extent of ab- product that is the subject of an ap-
sorption, the half-life of the thera- proved new drug application and that
peutic moiety in vivo, and the rate of contains the same active drug ingre-
excretion and/or metabolism. Dose pro- dient or therapeutic moiety, if the new
portionality of the active drug ingre- formulation, new dosage form, or new
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Food and Drug Administration, HHS § 320.25
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§ 320.26 21 CFR Ch. I (4–1–09 Edition)
shall be shown to meet all compendial (ii) The total area under the curve for
or other applicable standards of iden- a time period at least three times the
tity, strength, quality, and purity, in- half-life of the active drug ingredient
cluding potency and, where applicable, or therapeutic moiety, or its metabo-
content uniformity, disintegration lite(s), measured.
times, and dissolution rates. (2) In a study comparing oral dosage
(2) Samples of the drug product to be forms, the sampling times should be
tested shall be manufactured using the identical.
same equipment and under the same (3) In a study comparing an intra-
conditions as those used for full-scale venous dosage form and an oral dosage
production. form, the sampling times should be
those needed to describe both:
[42 FR 1648, Jan. 7, 1977, as amended at 67 FR (i) The distribution and elimination
77674, Dec. 19, 2002] phase of the intravenous dosage form;
and
§ 320.26 Guidelines on the design of a
single-dose in vivo bioavailability (ii) The absorption and elimination
or bioequivalence study. phase of the oral dosage form.
(4) In a study comparing drug deliv-
(a) Basic principles. (1) An in vivo bio- ery systems other than oral or intra-
availability or bioequivalence study venous dosage forms with an appro-
should be a single-dose comparison of priate reference standard, the sampling
the drug product to be tested and the times should be based on valid sci-
appropriate reference material con- entific reasons.
ducted in normal adults. (d) Collection of urine samples. When
(2) The test product and the reference comparison of the test product and the
material should be administered to reference material is to be based on cu-
subjects in the fasting state, unless mulative urinary excretion-time
some other approach is more appro- curves, unless some other approach is
priate for valid scientific reasons. more appropriate for valid scientific
(b) Study design. (1) A single-dose reasons, samples of the urine should be
study should be crossover in design, collected with sufficient frequency to
unless a parallel design or other design permit an estimate of the rate and ex-
is more appropriate for valid scientific tent of urinary excretion of the active
reasons, and should provide for a drug drug ingredient or therapeutic moiety,
elimination period. or its metabolite(s), measured.
(2) Unless some other approach is ap- (e) Measurement of an acute pharma-
propriate for valid scientific reasons, cological effect. (1) When comparison of
the drug elimination period should be the test product and the reference ma-
either: terial is to be based on acute pharma-
(i) At least three times the half-life cological effect-time curves, measure-
of the active drug ingredient or thera- ments of this effect should be made
peutic moiety, or its metabolite(s), with sufficient frequency to permit a
measured in the blood or urine; or reasonable estimate of the total area
(ii) At least three times the half-life under the curve for a time period at
of decay of the acute pharmacological least three times the half-life of decay
effect. of the pharmacological effect, unless
(c) Collection of blood samples. (1) some other approach is more appro-
When comparison of the test product priate for valid scientific reasons.
and the reference material is to be (2) The use of an acute pharma-
based on blood concentration time cological effect to determine bio-
curves, unless some other approach is availability may further require dem-
more appropriate for valid scientific onstration of dose-related response. In
reasons, blood samples should be taken such a case, bioavailability may be de-
with sufficient frequency to permit an termined by comparison of the dose-re-
estimate of both: sponse curves as well as the total area
(i) The peak concentration in the under the acute pharmacological ef-
blood of the active drug ingredient or fect-time curves for any given dose.
therapeutic moiety, or its metabo- [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
lite(s), measured; and 77674, Dec. 19, 2002]
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Food and Drug Administration, HHS § 320.27
§ 320.27 Guidelines on the design of a (ii) At least five times the half-life of
multiple-dose in vivo bioavailability decay of the acute pharmacological ef-
study. fect.
(a) Basic principles. (1) In selected cir- (c) Achievement of steady-state condi-
cumstances it may be necessary for the tions. Whenever a multiple-dose study
test product and the reference material is conducted, unless some other ap-
to be compared after repeated adminis- proach is more appropriate for valid
tration to determine steady-state lev- scientific reasons, sufficient doses of
els of the active drug ingredient or the test product and reference material
therapeutic moiety in the body. should be administered in accordance
(2) The test product and the reference with the labeling to achieve steady-
material should be administered to state conditions.
subjects in the fasting or nonfasting (d) Collection of blood or urine samples.
state, depending upon the conditions (1) Whenever comparison of the test
reflected in the proposed labeling of product and the reference material is
the test product. to be based on blood concentration-
time curves at steady state, appro-
(3) A multiple-dose study may be re-
priate dosage administration and sam-
quired to determine the bioavailability
pling should be carried out to docu-
of a drug product in the following cir-
ment attainment of steady state.
cumstances:
(2) Whenever comparison of the test
(i) There is a difference in the rate of
product and the reference material is
absorption but not in the extent of ab-
to be based on cumulative urinary ex-
sorption.
cretion-time curves at steady state, ap-
(ii) There is excessive variability in propriate dosage administration and
bioavailability from subject to subject. sampling should be carried out to docu-
(iii) The concentration of the active ment attainment of steady state.
drug ingredient or therapeutic moiety, (3) A more complete characterization
or its metabolite(s), in the blood re- of the blood concentration or urinary
sulting from a single dose is too low for excretion rate during the absorption
accurate determination by the analyt- and elimination phases of a single dose
ical method. administered at steady-state is encour-
(iv) The drug product is an extended aged to permit estimation of the total
release dosage form. area under concentration-time curves
(b) Study design. (1) A multiple-dose or cumulative urinary excretion-time
study should be crossover in design, curves and to obtain pharmacokinetic
unless a parallel design or other design information, e.g., half-life or blood
is more appropriate for valid scientific clearance, that is essential in pre-
reasons, and should provide for a drug paring adequate labeling for the drug
elimination period if steady-state con- product.
ditions are not achieved. (e) Steady-state parameters. (1) In cer-
(2) A multiple-dose study is not re- tain instances, e.g., in a study involv-
quired to be of crossover design if the ing a new drug entity, blood clearances
study is to establish dose proportion- at steady-state obtained in a multiple-
ality under a multiple-dose regimen or dose study should be compared to blood
to establish the pharmacokinetic pro- clearances obtained in a single-dose
file of a new drug product, a new drug study to support adequate dosage rec-
delivery system, or an extended release ommendations.
dosage form. (2) In a linear system, the area under
(3) If a drug elimination period is re- the blood concentration-time curve
quired, unless some other approach is during a dosing interval in a multiple-
more appropriate for valid scientific dose steady-state study is directly pro-
reasons, the drug elimination period portional to the fraction of the dose ab-
should be either: sorbed and is equal to the cor-
(i) At least five times the half-life of responding ‘‘zero to infinity’’ area
the active drug ingredient or thera- under the curve for a single-dose study.
peutic moiety, or its active metabo- Therefore, when steady-state condi-
lite(s), measured in the blood or urine; tions are achieved, a comparison of
or blood concentrations during a dosing
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§ 320.28 21 CFR Ch. I (4–1–09 Edition)
interval may be used to define the frac- fluids or excretory products produced
tion of the active drug ingredient or by a single dose of the test product,
therapeutic moiety absorbed. two or more single doses may be given
(3) Other methods based on valid sci- together to produce higher concentra-
entific reasons should be used to deter- tion if the requirements of § 320.31 are
mine the bioavailability of a drug prod- met.
uct having dose-dependent kinetics
(non-linear system). [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
(f) Measurement of an acute pharma- 77674, Dec. 19, 2002]
cological effect. When comparison of the
test product and the reference material § 320.30 Inquiries regarding bio-
availability and bioequivalence re-
is to be based on acute pharma-
quirements and review of protocols
cological effect-time curves, measure- by the Food and Drug Administra-
ments of this effect should be made tion.
with sufficient frequency to dem-
onstrate a maximum effect and a lack (a) The Commissioner of Food and
of significant difference between the Drugs strongly recommends that, to
test product and the reference mate- avoid the conduct of an improper study
rial. and unnecessary human research, any
person planning to conduct a bio-
[42 FR 1648, Jan. 7, 1977, as amended at 67 FR
77674, Dec. 19, 2002] availability or bioequivalence study
submit the proposed protocol for the
§ 320.28 Correlation of bioavailability study to FDA for review prior to the
with an acute pharmacological ef- initiation of the study.
fect or clinical evidence. (b) FDA may review a proposed pro-
Correlation of in vivo bioavailability tocol for a bioavailability or bioequiva-
data with an acute pharmacological ef- lence study and will offer advice with
fect or clinical evidence of safety and respect to whether the following condi-
effectiveness may be required if needed tions are met:
to establish the clinical significance of (1) The design of the proposed bio-
a special claim, e.g., in the case of an availability or bioequivalence study is
extended release preparation. appropriate.
[42 FR 1648, Jan. 7, 1977, as amended at 67 FR (2) The reference material to be used
77674, Dec. 19, 2002] in the bioavailability or bioequivalence
study is appropriate.
§ 320.29 Analytical methods for an in
vivo bioavailability or bioequiva- (3) The proposed chemical and statis-
lence study. tical analytical methods are adequate.
(a) The analytical method used in an (c)(1) General inquiries relating to in
in vivo bioavailability or bioequiva- vivo bioavailability requirements and
lence study to measure the concentra- methodology shall be submitted to the
tion of the active drug ingredient or Food and Drug Administration, Center
therapeutic moiety, or its active me- for Drug Evaluation and Research, Of-
tabolite(s), in body fluids or excretory fice of Clinical Pharmacology, 10903
products, or the method used to meas- New Hampshire Ave., Silver Spring,
ure an acute pharmacological effect MD 20993–0002.
shall be demonstrated to be accurate (2) General inquiries relating to bio-
and of sufficient sensitivity to meas- equivalence requirements and method-
ure, with appropriate precision, the ac- ology shall be submitted to the Food
tual concentration of the active drug and Drug Administration, Center for
ingredient or therapeutic moiety, or its Drug Evaluation and Research, Divi-
active metabolite(s), achieved in the sion of Bioequivalence (HFD–650), 7500
body. Standish Pl., Rockville, MD 20855–2773.
(b) When the analytical method is
not sensitive enough to measure accu- [57 FR 18000, Apr. 28, 1992, as amended at 67
rately the concentration of the active FR 77674, Dec. 19, 2002; 74 FR 13114, Mar. 26,
drug ingredient or therapeutic moiety, 2009]
or its active metabolite(s), in body
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Food and Drug Administration, HHS § 320.32
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§ 320.33 21 CFR Ch. I (4–1–09 Edition)
198
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Food and Drug Administration, HHS § 320.38
199
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§ 320.38 21 CFR Ch. I (4–1–09 Edition)
(1) If the formulation of the test arti- ple from which the reserve sample was
cle is the same as the formulation(s) obtained was used.
used in the clinical studies dem- (f) Authorized FDA personnel will or-
onstrating substantial evidence of safe- dinarily collect reserve samples di-
ty and effectiveness for the test arti- rectly from the applicant or contract
cle’s claimed indications, a reserve research organization at the storage
sample of the test article used to con- site during a preapproval inspection. If
duct an in vivo bioavailability study authorized FDA personnel are unable
comparing the test article to a ref- to collect samples, FDA may require
erence oral solution, suspension, or in- the applicant or contract research or-
jection. ganization to submit the reserve sam-
(2) If the formulation of the test arti- ples to the place identified in the agen-
cle differs from the formulation(s) used cy’s request. If FDA has not collected
in the clinical studies demonstrating or requested delivery of a reserve sam-
substantial evidence of safety and ef-
ple, or if FDA has not collected or re-
fectiveness for the test article’s
quested delivery of any portion of a re-
claimed indications, a reserve sample
serve sample, the applicant or contract
of the test article and of the reference
research organization shall retain the
standard used to conduct an in vivo
sample or remaining sample for the 5-
bioequivalence study comparing the
test article to the formulation(s) (ref- year period specified in paragraph (e)
erence standard) used in the clinical of this section.
studies. (g) Upon release of the reserve sam-
(3) For a new formulation, new dos- ples to FDA, the applicant or contract
age form, or a new salt or ester of an research organization shall provide a
active drug ingredient or therapeutic written assurance that, to the best
moiety that has been approved for mar- knowledge and belief of the individual
keting, a reserve sample of the test ar- executing the assurance, the reserve
ticle and of the reference standard used samples came from the same samples
to conduct an in vivo bioequivalence as used in the specific bioavailability
study comparing the test article to a or bioequivalence study identified by
marketed product (reference standard) the agency. The assurance shall be exe-
that contains the same active drug in- cuted by an individual authorized to
gredient or therapeutic moiety. act for the applicant or contract re-
(c) Each reserve sample shall consist search organization in releasing the re-
of a sufficient quantity to permit FDA serve samples to FDA.
to perform five times all of the release (h) A contract research organization
tests required in the application or may contract with an appropriate,
supplemental application. independent third party to provide
(d) Each reserve sample shall be ade- storage of reserve samples provided
quately identified so that the reserve that the sponsor of the study has been
sample can be positively identified as notified in writing of the name and ad-
having come from the same sample as dress of the facility at which the re-
used in the specific bioavailability serve samples will be stored.
study. (i) If a contract research organization
(e) Each reserve sample shall be conducting a bioavailability or bio-
stored under conditions consistent equivalence study that requires reserve
with product labeling and in an area sample retention under this section or
segregated from the area where testing § 320.63 goes out of business, it shall
is conducted and with access limited to transfer its reserve samples to an ap-
authorized personnel. Each reserve propriate, independent third party, and
sample shall be retained for a period of
shall notify in writing the sponsor of
at least 5 years following the date on
the study of the transfer and provide
which the application or supplemental
the study sponsor with the name and
application is approved, or, if such ap-
address of the facility to which the re-
plication or supplemental application
serve samples have been transferred.
is not approved, at least 5 years fol-
lowing the date of completion of the [58 FR 25927, Apr. 28, 1993, as amended at 64
bioavailability study in which the sam- FR 402, Jan. 5, 1999]
200
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Food and Drug Administration, HHS § 328.10
201
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