[Federal Register Volume 63, Number 223 (Thursday, November 19, 1998)]
[Proposed Rules]
[Pages 64222-64228]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-30880]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 314 and 320
[Docket No. 98N-0778]
Bioavailability and Bioequivalence Requirements; Abbreviated
Applications; Proposed Revisions
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to revise
its regulations on bioavailability and bioequivalence and on the
content and format of an abbreviated application to reflect current FDA
policy and to correct certain typographical and inadvertent errors.
This action is intended to improve the accuracy and clarity of the
regulations.
DATES: Written comments by February 2, 1999. FDA proposes that any
final rule based on this proposal become effective 60 days after its
date of publication in the Federal Register.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Christine F. Rogers, Center for Drug
Evaluation and Research (HFD-7), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-2041.
SUPPLEMENTARY INFORMATION:
I. Background
FDA regulations require persons submitting a new drug application
(NDA) to provide bioavailability information (21 CFR 314.50(c)(2)(vi)
and (d)(3)), and persons submitting an abbreviated new drug application
(ANDA) or abbreviated antibiotic application (AADA) to provide
information pertaining to bioavailability and bioequivalence
(Sec. 314.94(a)(7) and (d)(3) (21 CFR 314.94(a)(7) and (d)(3))).
FDA regulations in part 320 (21 CFR part 320) establish definitions
and requirements for bioavailability and bioequivalence studies. FDA
finalized the bioavailability and bioequivalence regulations on January
7, 1977 (42 FR 1624), and amended these regulations on April 28, 1992
(57 FR 17950). The 1992 amendments were designed to reflect statutory
changes resulting from the Drug Price Competition and Patent Term
Restoration Act of 1984 (Pub. L. 98-417).
Bioavailability, in general, refers to 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 (Sec. 320.1(a)). Bioequivalence, in general, refers to
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. Where there is an
intentional difference in rate (e.g., in certain controlled release
dosage forms), certain pharmaceutical equivalents or alternatives may
be considered bioequivalent if there is no significant difference in
the extent to which the active ingredient or moiety from each product
becomes available at the site of drug action (Sec. 320.1(e)).
II. Description of the Proposed Rule
The proposed rule would revise FDA regulations pertaining to
abbreviated applications, bioavailability, and bioequivalence to
reflect current agency policy, to correct typographical and inadvertent
errors, and to clarify existing provisions. The proposed amendments
follow.
Section 314.94(a)(9) establishes information requirements for the
chemistry, manufacturing, and controls section of an abbreviated
application. Section 314.94(a)(9) provides that an abbreviated
application may have different inactive ingredients than the reference
listed drug as long as the applicant identifies and characterizes the
inactive ingredients in the proposed drug product and provides
information demonstrating that the inactive ingredients do not affect
the safety of the drug product. The proposed rule would amend this
section to recognize the possibility that the use of different inactive
ingredients may also affect a product's efficacy.
Section 314.94(a)(9)(v) establishes the requirements for inactive
ingredient changes permitted in drug products intended for topical use.
The proposed rule would revise this section to include solutions for
aerosolization or nebulization as well as nasal solutions. This change
is intended to clarify that these solutions may be characterized as
drug products intended for topical use.
[[Page 64223]]
Section 314.127 (21 CFR 314.127) sets forth the reasons why FDA
would refuse to approve an ANDA. The proposed rule would revise
Sec. 314.127(a)(8) to clarify that, consistent with current FDA policy,
the applicant must show that different inactive ingredients would not
affect a product's efficacy, in addition to the currently required
showing for safety. This revision is necessary because a change in
inactive ingredients may affect safety or efficacy or both. As the
agency stated in the preamble to the proposed rule implementing the
Drug Price Competition and Patent Term Restoration Act of 1984, ``[i]t
is well established that changing the inactive ingredients in a drug
can adversely affect the drug's safety or effectiveness.'' (See 54 FR
28872 at 28902, July 10, 1989.) For example, an inactive ingredient
that increases or decreases an active ingredient's efficacy may affect
the safety of the drug product as well. If a drug is not achieving its
therapeutic purpose, the drug may be unsafe for use. An ineffective
drug may cause a patient to unwittingly delay effective treatment.
Thus, safety and effectiveness are, to a great extent, intertwining
principles.
Section 320.1(c) defines ``pharmaceutical equivalents'' as:
* * * drug products that contain identical amounts of the
identical active drug ingredient, i.e., the same salt or ester of
the same therapeutic moiety, in identical dosage forms, but not
necessarily containing the same inactive ingredients, and that meet
the identical compendial or other applicable standard of identity,
strength, quality, and purity, including potency and, where
applicable, content uniformity, disintegration times and/or
dissolution rates.
This definition has been the source of some confusion with regard
to certain modified release systems, prefilled syringes, and other drug
products that contain a reservoir that facilitates delivery or where
residual volume may vary. In such products, the agency does not
consider the amount that facilitates the action of the delivery system,
but by design is not intended to be delivered to the site of drug
action or to have any direct therapeutic effect, to be ``active
ingredient'' for the purposes of evaluating the pharmaceutical
equivalence of a drug product.
Therefore, to clarify the definition of ``pharmaceutical
equivalents'' with regard to certain drug products such as prefilled
syringes and those that use modified release systems, the agency is
proposing to revise the definition of ``pharmaceutical equivalents'' in
Sec. 320.1(c) to state:
* * * drug products in identical dosage forms that contain
identical amounts of the identical active drug ingredient, i.e., the
same salt or ester of the same therapeutic moiety or, in the case of
modified release dosage forms that require a reservoir or overage or
such forms as prefilled syringes where residual volume may vary,
that deliver identical amounts of the active drug ingredient over
the identical dosing period; do not necessarily contain the same
inactive ingredients; and meet the identical compendial or other
applicable standard of identity, strength, quality, and purity,
including potency and, where applicable, content uniformity,
disintegration times, and/or dissolution rates.
Subpart B of part 320 describes procedures for determining the
bioavailability or bioequivalence of drug products, and refers to
evidence that ``demonstrates'' in vivo bioavailability and
bioequivalence. The proposed rule would modify current Secs. 320.21,
320.22, 320.23, 320.24, and 320.25 to clarify that although
bioequivalence may be ``demonstrated'' or ``established,''
bioavailability can only be ``measured.'' These verb changes also
require that the words ``in vivo'' precede the word ``bioequivalence.''
Section 320.21 sets forth the requirements for submission of in
vivo bioavailability and bioequivalence data. Section 320.21(b)(1)
provides that any person submitting an abbreviated application must
submit evidence demonstrating that the proposed drug product is
bioequivalent to the reference listed drug or, under Sec. 320.21(b)(2),
provide ``[i]nformation to show that the drug product is bioequivalent
to the reference listed drug which would permit FDA to waive the
submission of evidence demonstrating bioequivalence * * *.'' The
proposed rule would revise Sec. 320.21(b)(2) to clarify that the waiver
would only pertain to the submission of evidence demonstrating the in
vivo determination of bioequivalence.
Section 320.21(c)(1) provides that any person submitting a
supplemental application to FDA must provide evidence or information
regarding the product's bioavailability or bioequivalence if the
supplemental application proposes ``[a] change in the manufacturing
process, including a change in product formulation or dosage strength,
beyond the variations provided for in the approved application.'' The
proposed rule would amend this provision to include a change in the
manufacturing site because such a change may affect the bioavailability
or bioequivalence of the drug product because of equipment, personnel,
or environmental changes.
Section 320.21(d) states that ``FDA may approve a full new drug
application * * * that does not contain evidence of in vivo
bioavailability or information to permit waiver of the requirement for
in vivo bioavailability data,'' if, among other things, ``[t]he
application was under review by FDA on July 7, 1977''
(Sec. 320.21(d)(1).) The agency is proposing to remove this paragraph
because it has become outdated.
Section 320.21(f) inaccurately includes a reference to criteria set
forth in Sec. 320.24 as containing information under which FDA could
waive the requirement for submission of evidence demonstrating in vivo
bioavailability or bioequivalence. The proposed rule would replace the
reference to Sec. 320.24 with Sec. 320.22.
Proposed Sec. 320.22(a) would address another typographical error.
Current Sec. 320.22(a) states that ``[e]xcept as provided in paragraph
(g) of this section,'' FDA shall waive the requirement for the
submission of evidence of in vivo bioavailability or bioequivalence
under certain conditions. The proposed rule would substitute paragraph
(f) for the reference to paragraph (g).
Section 320.22(b) sets forth the criteria under which a drug
product's in vivo bioavailability or bioequivalence may be considered
self-evident based on other data in an application showing that the
proposed drug product is identical in certain respects to the ``drug
product that is the subject of an approved full new drug application''
(see Sec. 320.22(b)(1)(ii), (b)(2)(ii), and (b)(3)(ii)). The proposed
rule would replace ``approved full new drug application'' with
``approved full new drug application or abbreviated new drug
application.'' This revision recognizes those instances when an
approved abbreviated new drug application might be the reference listed
drug because there is no approved full new drug application. The
proposed rule would make a similar change to Sec. 320.22(b)(3)(iii)
because this provision also refers to a ``drug product that is the
subject of the approved full new drug application * * *.''
Section 320.22(b)(3)(i) sets forth the criteria for waiver of the
in vivo bioavailability or bioequivalence of a drug product that is ``a
solution for application to the skin, an oral solution, elixir, syrup,
tincture, or similar other solubilized form'' intended for either local
or systemic effect. The proposed rule would amend Sec. 320.22(b)(3)(i)
to include a ``solution for aerosolization or nebulization'' and a
``nasal solution'' to clarify that ``similar other solubilized form''
includes solutions for aerosolization or nebulization and nasal
solutions.
Section 320.22(c) provides that ``FDA shall waive the requirement
for the submission of evidence demonstrating
[[Page 64224]]
the in vivo bioavailability of a solid oral dosage form (other than an
enteric coated or controlled release dosage form) * * *'' unless, among
other things, ``FDA has evaluated the drug product under the criteria
set forth in Sec. 320.32 * * *.'' The reference to Sec. 320.32 is a
typographical error. The proposed rule would refer to Sec. 320.33
because the relevant criteria are found in that provision. In addition,
the proposed rule would clarify that FDA may waive this requirement not
only for the submission of evidence of in vivo bioavailability but also
for the submission of evidence of in vivo bioequivalence.
The proposed rule would also amend Sec. 320.22(c) because ``delayed
release'' is the preferred terminology for ``enteric coated'' and
``extended release'' is the preferred terminology for ``controlled
release.''
Under Sec. 320.22(e), ``FDA, for good cause, may waive a
requirement for the submission of evidence of in vivo bioavailability
if waiver is compatible with the protection of the public health * *
*.'' When the agency revised and finalized the regulations in 1992, it
intended that Sec. 320.22(e) clearly include waiver of in vivo
bioequivalence testing, as the heading of the section suggests. Indeed,
waiver of the submission of in vivo bioavailability data is related to
waiver of in vivo bioequivalence testing in that bioequivalence is an
assessment of comparative bioavailability. Because there may be some
confusion about the scope of Sec. 320.22(e), the proposed rule would
clarify that FDA may, for good cause, waive not only the submission of
evidence of in vivo bioavailability but also the submission of evidence
of in vivo bioequivalence, if such a waiver is compatible with the
protection of the public health. Such a waiver may be appropriate in
cases where an abbreviated application uses inactive ingredients
different from those in the reference listed drug (see
Sec. 314.94(a)(9)), and thus the other provisions regarding a waiver of
a the requirement for the submission of evidence of in vivo
bioavailability or bioequivalence do not apply. In such cases, a waiver
of the submission of evidence of in vivo bioavailability or
bioequivalence may, for good cause, be granted if compatible with the
protection of the public health.
Section 320.24 sets forth the various types of evidence needed to
establish bioavailability or bioequivalence. The agency is removing
Sec. 320.24(b)(1)(iii) because FDA does not encourage the use of
animals in vivo bioavailability studies. Section 320.24(b)(5), which
focuses on one method, in vitro testing, contains a typographical
error, stating that the in vitro test acceptable to FDA is ``unusually
a dissolution rate test.'' The proposed rule would replace
``unusually'' with ``usually.''
Section 320.25 provides guidelines for the conduct of an in vivo
bioavailability study. Section 320.25(a)(2) provides that ``[a]n in
vivo bioavailability study shall not be conducted in humans if an
appropriate animal model exists and correlation of results in animals
and humans has been demonstrated * * *.'' The agency is proposing to
remove Sec. 320.25(a)(2) because FDA does not encourage the use of
animals in vivo bioavailability studies.
Section 320.25(d)(1) describes the purpose of a bioavailability
study involving a drug product containing an active drug ingredient or
therapeutic moiety that has not been approved for marketing. The agency
has determined that Sec. 320.25(d)(1) is inaccurate because it actually
describes the purpose of a pharmacokinetic study, rather than a
bioavailability study. Thus, the proposed rule would revise the
introductory text of Sec. 320.25(d)(1) to read ``An in vivo
bioavailability study involving a drug product containing an active
drug ingredient or therapeutic moiety that has not been approved for
marketing can be used to measure the following pharmacokinetic data: *
* *.''
Section 320.25(e)(1) describes the purpose of an in vivo
bioavailability study involving a drug product that is a new
formulation, a new dosage form, or a new salt or ester of an active
drug ingredient or therapeutic moiety that has been approved for
marketing. The agency has determined that Sec. 320.25(e)(1) is
inaccurate because it also describes the purpose of a pharmacokinetic
study, not a bioavailability study. Thus, the proposed rule would
revise the introductory text of Sec. 320.25(e)(1) to read ``An in vivo
bioavailability study involving a drug product that is a new
formulation, a new dosage form, or a new salt or ester of an active
drug ingredient or therapeutic moiety that has been approved for
marketing can be used to: * * *.''
Section 320.26 provides guidance on the design of a single-dose in
vivo bioavailability study, and Sec. 320.27 provides guidance on the
design of a multiple-dose in vivo bioavailability study. The proposed
rule would add the word ``bioequivalence'' after ``bioavailability''
throughout these two sections because Secs. 320.26 and 320.27 are also
applicable to in vivo bioequivalence studies. This revision reflects
current FDA policy. The proposed rule would also amend Secs. 320.28 and
320.29 to include reference to bioequivalence because these sections
are also applicable to in vivo bioequivalence studies.
The proposed rule would also amend Sec. 320.26(b)(2)(i) by
replacing ``three'' with ``five.'' The proposed rule would also insert
the word ``active'' before ``metabolite(s)'' in Secs. 320.26(b)(2)(i)
and 320.27(b)(3)(i). FDA is proposing these revisions because the drug
elimination period (wash-out period) of three times the half-life of
the active drug ingredient or therapeutic moiety, or its active
metabolite(s), is inadequate, and because current analytical methods
exist that usually are capable of detecting drug concentrations after
five times the half-life of the active drug ingredient or therapeutic
moiety, or its active metabolite(s).
Section 320.27(d)(1) states that, for the collection of blood
samples during multiple-dose in vivo bioavailability studies, the
maximum (Cmax) and minimum (Cmin) values should be defined on 2 or more
consecutive days to establish that steady-state conditions are
achieved. FDA no longer uses Cmax values in the determination of
steady-state conditions and, in some cases, the predose trough level
may not be the observed Cmin value. In addition, FDA recommends that
sampling be done for at least 3 consecutive days. Therefore, the
proposed rule would revise Sec. 320.27(d)(1) to state:
Whenever comparison of the test product and the reference
material is to be based on blood concentration-time curves at
steady-state, sufficient samples of blood should be taken to define
adequately the predose blood concentration on 3 or more consecutive
days to establish that steady-state conditions are achieved.
Section 320.27(d)(2) states that ``[w]henever comparison of the
test product and the reference material is to be based on cumulative
urinary excretion-time curves at steady-state, sufficient samples of
urine should be taken to define the rate and extent of urinary
excretion on 2 or more consecutive days to establish that steady-state
conditions are achieved.'' For the reasons stated previously, the
proposed rule would revise this paragraph to state:
Whenever comparison of the test product and the reference
material is to be based on cumulative urinary excretion-time curves
at steady-state, sufficient samples of urine should be taken to
define the rate and extent of urinary excretion on 3 or more
consecutive days to establish that steady-state conditions are
achieved.
Section 320.30(c)(1) directs inquiries on bioavailability to the
Division of Biopharmaceutics in the Center for Drug Evaluation and
Research. The proposal
[[Page 64225]]
would update the name of the Division of Biopharmaceutics because it is
now called the ``Office of Clinical Pharmacology and Biopharmaceutics''
(HFD-850).
Section 320.30(c)(2) directs inquiries on bioequivalence
requirements and methodology to the Division of Bioequivalence in the
Center for Drug Evaluation and Research. The proposal would update the
mailing address for the Division of Bioequivalence because it is now
located at Metro Park North II, 7500 Standish Pl., Rockville, MD 20855-
2773.
Section 320.31 discusses the applicability of the investigational
new drug application requirements to certain bioavailability or
bioequivalence studies. Although FDA intended that this section apply
to bioavailability or bioequivalence studies, Sec. 320.31(b) only
refers to bioavailability studies. The proposal would insert the words
``or bioequivalence'' after the word ``bioavailability'' in the
introductory text of Sec. 320.31(b) to clarify that this section
applies to bioequivalence studies as well.
Broader issues concerning FDA's interpretation and application of
the regulations applicable to bioequivalence issues have recently been
the subject of controversy. The ability to characterize and quantify
the components of drug products has evolved and continues to evolve
with advances in the science of analytical chemistry. A more refined
characterization of a drug product may complicate determinations about
the components or quantity of components that may affect the safety of
the drug product or contribute to its pharmacological effect. Changes
to definitional concepts such as active and inactive ingredients are
beyond the scope of these, for the most part, technical revisions to
the regulations. However, FDA intends to address such issues in a
future proposal.
III. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages). Under the Regulatory Flexibility Act, unless an agency
certifies that a rule will not have a significant impact on small
entities, the agency must analyze regulatory options that would
minimize the impact of the rule on small entities. Title II of the
Unfunded Mandates Reform Act (Pub. L. 104-114) (in section 202)
requires that agencies prepare an assessment of anticipated costs and
benefits before proposing any rule that may result in an expenditure in
any 1 year by State, local, and tribal governments, in the aggregate,
or by the private sector, of $100 million or more (adjusted annually
for inflation).
The agency has reviewed this proposed rule and has determined that
it is consistent with the regulatory philosophy and principles
identified in Executive Order 12866, and these two statutes. With
respect to the Regulatory Flexibility Act, the agency certifies that
the rule will not have a significant economic impact on a substantial
number of small entities. Because the proposed rule does not impose any
mandates on State, local, or tribal governments, or the private sector
that will result in a 1-year expenditure of $100 million or more, FDA
is not required to perform a cost-benefit analysis under the Unfunded
Mandates Reform Act.
The proposed rule would amend the bioavailability and
bioequivalence regulations to reflect current FDA policy.
IV. Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed rule contains no
collections of information. Therefore, clearance by the Office of
Management and Budget under the Paperwork Reduction Act of 1995 is not
required.
V. Environmental Impact
The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VI. Request for Comments
Interested persons may, on or before February 2, 1999, submit to
the Dockets Management Branch (address above) written comments
regarding this proposal. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments are to
be identified with the docket number found in brackets in the heading
of this document. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.
List of Subjects
21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
21 CFR Part 320
Drugs, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and the
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 314 and 320 be amended as follows:
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN
ANTIBIOTIC DRUG
1. The authority citation for 21 CFR part 314 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 371,
374, 379e.
2. Section 314.94 is amended in paragraph (a)(9)(ii) and the second
sentence of paragraphs (a)(9)(iii) and (a)(9)(iv) by adding after the
word ``safety'' the phrase ``or efficacy'' each time it appears, and by
revising paragraph (a)(9)(v) to read as follows:
Sec. 314.94 Content and format of an abbreviated application.
* * * * *
(a) * * *
(9) * * *
(v) Inactive ingredient changes permitted in drug products intended
for topical use. Generally, a drug product intended for topical use,
solutions for aerosolization or nebulization, and nasal solutions shall
contain the same inactive ingredients as the reference listed drug
identified by the applicant under paragraph (a)(3) of this section.
However, an abbreviated application may include different inactive
ingredients provided that the applicant identifies and characterizes
the differences and provides information demonstrating that the
differences do not affect the safety or efficacy of the proposed drug
product.
* * * * *
Sec. 314.127 [Amended]
3. Section 314.127 Refusal to approve an abbreviated new drug
application is amended in the introductory text of paragraph
(a)(8)(ii)(A), and in paragraphs (a)(8)(ii)(B) and (a)(8)(ii)(C) by
adding after the word ``safety'' the phrase ``or efficacy'' each time
it appears.
[[Page 64226]]
PART 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS
4. The authority citation for 21 CFR part 320 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 355, 357, 371.
5. Section 320.1 is amended by revising paragraph (c) to read as
follows:
Sec. 320.1 Definitions.
* * * * *
(c) Pharmaceutical equivalents means drug products in identical
dosage forms that contain identical amounts of the identical active
drug ingredient, i.e., the same salt or ester of the same therapeutic
moiety, or, in the case of modified release dosage forms that require a
reservoir or overage or such forms as prefilled syringes where residual
volume may vary, that deliver identical amounts of the active drug
ingredient over the identical dosing period; do not necessarily contain
the same inactive ingredients; and meet the identical compendial or
other applicable standard of identity, strength, quality, and purity,
including potency and, where applicable, content uniformity,
disintegration times, and/or dissolution rates.
* * * * *
6. Section 320.21 is amended by removing paragraph (d)(1) and
redesignating paragraphs (d)(2) and (d)(3) as paragraphs (d)(1) and
(d)(2), respectively, and by revising newly redesignated (d)(2)(i) and
(d)(2)(ii); and by revising paragraphs (a)(1), (a)(2), (b)(1), (b)(2),
(c)(1), (e), and (f), the introductory text of paragraph (g), and
paragraphs (g)(2) and (h) to read as follows:
Sec. 320.21 Requirements for submission of in vivo bioavailability
and bioequivalence data.
(a) * * *
(1) Evidence measuring the in vivo bioavailability of the drug
product that is the subject of the application; or
(2) Information to permit FDA to waive the submission of evidence
measuring in vivo bioavailability.
(b) * * *
(1) Evidence demonstrating that the drug product that is the
subject of the abbreviated new drug application is bioequivalent to the
reference listed drug (defined in Sec. 314.3(b) of this chapter); or
(2) Information to show that the drug product is bioequivalent to
the reference listed drug which would permit FDA to waive the
submission of evidence demonstrating in vivo bioequivalence as provided
in paragraph (f) of this section.
(c) * * *
(1) A change in manufacturing site as well as a change in the
manufacturing process, including a change in product formulation or
dosage strength, beyond the variations provided for in the approved
application.
* * * * *
(d) * * *
(2) * * *
(i) Evidence measuring the in vivo bioavailability and
demonstrating the in vivo bioequivalence of the drug product that is
the subject of the application; or
(ii) Information to permit FDA to waive measurement of in vivo
bioavailability.
(e) Evidence measuring the in vivo bioavailability and
demonstrating the in vivo bioequivalence of a drug product shall be
obtained using one of the approaches for determining bioavailability
set forth in Sec. 320.24.
(f) Information to permit FDA to waive the submission of evidence
measuring the in vivo bioavailability or demonstrating the in vivo
bioequivalence shall meet the criteria set forth in Sec. 320.22.
(g) Any person holding an approved full or abbreviated new drug
application shall submit to FDA a supplemental application containing
new evidence measuring the in vivo bioavailability or demonstrating the
in vivo bioequivalence of the drug product that is the subject of the
application if notified by FDA that:
* * * * *
(2) There are data measuring significant intra-batch and batch-to-
batch variability, e.g., plus or minus 25 percent, in the
bioavailability of the drug product.
(h) The requirements of this section regarding the submission of
evidence measuring the in vivo bioavailability or demonstrating the in
vivo bioequivalence apply only to a full or abbreviated new drug
application or a supplemental application for a finished dosage
formulation.
7. Section 320.22 is amended by revising paragraph (a), the second
sentence of paragraph (b), paragraphs (b)(1)(ii), (b)(2)(ii),
(b)(3)(i), (b)(3)(ii), (b)(3)(iii), and (c), the introductory text of
paragraph (d), paragraphs (d)(2)(i) and (d)(4)(i), and the first
sentence of paragraph (e) to read as follows:
Sec. 320.22 Criteria for waiver of evidence of in vivo bioavailability
or bioequivalence.
(a) Any person submitting a full or abbreviated new drug
application, or a supplemental application proposing any of the changes
set forth in Sec. 320.21(c), may request FDA to waive the requirement
for the submission of evidence measuring the in vivo bioavailability or
demonstrating the in vivo bioequivalence of the drug product that is
the subject of the application. An applicant shall submit a request for
waiver with the application. Except as provided in paragraph (f) of
this section, FDA shall waive the requirement for the submission of
evidence of in vivo bioavailability or bioequivalence if the drug
product meets any of the provisions of paragraphs (b), (c), (d), or (e)
of this section.
(b) * * * FDA shall waive the requirement for the submission of
evidence obtained in vivo measuring the bioavailability or
demonstrating the bioequivalence of these drug products. * * *
(1) * * *
(ii) Contains the same active and inactive ingredients in the same
concentration as a drug product that is the subject of an approved full
new drug application or abbreviated new drug application.
(2) * * *
(ii) Contains an active ingredient in the same dosage form as a
drug product that is the subject of an approved full new drug
application or abbreviated new drug application.
(3) * * *
(i) Is a solution for application to the skin, an oral solution,
elixir, syrup, tincture, a solution for aerosolization or nebulization,
a nasal solution, or similar other solubilized form.
(ii) Contains an active drug ingredient in the same concentration
and dosage form as a drug product that is the subject of an approved
full new drug application or abbreviated new drug application; and
(iii) Contains no inactive ingredient or other change in
formulation from the drug product that is the subject of the approved
full new drug application or abbreviated new drug application that may
significantly affect absorption of the active drug ingredient or active
moiety.
(c) FDA shall waive the requirement for the submission of evidence
measuring the in vivo bioavailability or demonstrating the in vivo
bioequivalence of a solid oral dosage form (other than a delayed
release or extended release dosage form) of a drug product determined
to be effective for at least one indication in a Drug Efficacy Study
Implementation notice or which is identical, related, or similar to
such a drug product under Sec. 310.6 of this chapter unless FDA has
evaluated the drug product under the criteria set forth in Sec. 320.33,
included the drug product in the Approved Drug Products with
Therapeutic Equivalence Evaluations List, and rated the drug product as
[[Page 64227]]
having a known or potential bioequivalence problem. A drug product so
rated reflects a determination by FDA that an in vivo bioequivalence
study is required.
(d) For certain drug products, bioavailability may be measured or
bioequivalence may be demonstrated by evidence obtained in vitro in
lieu of in vivo data. FDA shall waive the requirement for the
submission of evidence obtained in vivo measuring the bioavailability
or demonstrating the bioequivalence of the drug product if the drug
product meets one of the following criteria:
* * * * *
(2) * * *
(i) The bioavailability of this other drug product has been
measured;
* * * * *
(4) * * *
(i) The bioavailability of the other product has been measured; and
* * * * *
(e) FDA, for good cause, may waive a requirement for the submission
of evidence of in vivo bioavailability or bioequivalence if waiver is
compatible with the protection of the public health. * * *
* * * * *
8. Section 320.23 is amended by revising the section heading and
the first sentence of paragraph (a)(1) to read as follows:
Sec. 320.23 Basis for measuring in vivo bioavailability or
demonstrating bioequivalence.
(a)(1) The in vivo bioavailability of a drug product is measured if
the product's rate and extent of absorption, as determined by
comparison of measured parameters, e.g., concentration of the active
drug ingredient in the blood, urinary excretion rates, or
pharmacological effects, do not indicate a significant difference from
the reference material's rate and extent of absorption. * * *
* * * * *
9. Section 320.24 is amended by revising the section heading and
the first, second, and last sentences of paragraph (a), by removing
paragraph (b)(1)(iii), by revising the first, second, and last
sentences of paragraph (b)(4), paragraphs (b)(5) and (b)(6), and the
introductory text of paragraph (c) to read as follows:
Sec. 320.24 Types of evidence to measure bioavailability or establish
bioequivalence.
(a) Bioavailability may be measured or bioequivalence may be
demonstrated by several in vivo and in vitro methods. FDA may require
in vivo or in vitro testing, or both, to measure the bioavailability of
a drug product or establish the bioequivalence of specific drug
products. * * * The method used must be capable of measuring
bioavailability or establishing bioequivalence, as appropriate, for the
product being tested.
(b) * * *
(4) Well-controlled clinical trials that establish the safety and
effectiveness of the drug product, for purposes of measuring
bioavailability, or appropriately designed comparative clinical trials,
for purposes of demonstrating bioequivalence. This approach is the
least accurate, sensitive, and reproducible of the general approaches
for measuring bioavailability or demonstrating bioequivalence. * * *
This approach may also be considered sufficiently accurate for
measuring bioavailability or demonstrating bioequivalence of dosage
forms intended to deliver the active moiety locally, e.g., topical
preparations for the skin, eye, and mucous membranes; oral dosage forms
not intended to be absorbed, e.g., an antacid or radiopaque medium; and
bronchodilators administered by inhalation if the onset and duration of
pharmacological activity are defined.
(5) A currently available in vitro test acceptable to FDA (usually
a dissolution rate test) that ensures human in vivo bioavailability.
(6) Any other approach deemed adequate by FDA to measure
bioavailability or establish bioequivalence.
(c) FDA may, notwithstanding prior requirements for measuring
bioavailability or establishing bioequivalence, require in vivo testing
in humans of a product at any time if the agency has evidence that the
product:
* * * * *
10. Section 320.25 is amended by removing paragraph (a)(2), by
redesignating paragraph (a)(3) as paragraph (a)(2), and by revising
paragraph (d)(1), the introductory text of paragraph (e)(1), and
paragraph (e)(1)(i) to read as follows:
Sec. 320.25 Guidelines for the conduct of an in vivo bioavailability
study.
* * * * *
(d) Previously unmarketed active drug ingredients or therapeutic
moieties. (1) An in vivo bioavailability study involving a drug product
containing an active drug ingredient or therapeutic moiety that has not
been approved for marketing can be used to measure the following
pharmacokinetic data:
* * * * *
(e) New formulations of active drug ingredients or therapeutic
moieties approved for marketing. (1) An in vivo bioavailability study
involving a drug product that is a new dosage form, or a new salt or
ester of an active drug ingredient or therapeutic moiety that has been
approved for marketing can be used to:
(i) Measure the bioavailability of the new formulation, new dosage
form, or new salt or ester relative to an appropriate reference
material; and
* * * * *
11. Section 320.26 is amended by revising the section heading and
paragraphs (a)(1) and (b)(2)(i) to read as follows:
Sec. 320.26 Guidelines on the design of a single-dose in vivo
bioavailability or bioequivalence study.
(a) Basic principles. (1) An in vivo bioavailability or
bioequivalence study should be a single-dose comparison of the drug
product to be tested and the appropriate reference material conducted
in normal adults.
* * * * *
(b) * * *
(2) * * *
(i) At least five times the half-life of the active drug ingredient
or therapeutic moiety, or its active metabolite(s), measured in the
blood or urine; or
* * * * *
12. Section 320.27 is amended by revising the section heading,
introductory text of paragraph (a)(3), paragraphs (d)(1), (d)(2), and
(e)(3); and by adding in paragraph (b)(3)(i) the word ``active'' before
the word ``metabolite(s),'' to read as follows:
Sec. 320.27 Guidelines on the design of a multiple-dose in vivo
bioavailability or bioequivalence study.
(a) * * *
(3) A multiple-dose study may be required to determine the
bioavailability or bioequivalence of a drug product in the following
circumstances:
* * * * *
(d) Collection of blood or urine samples. (1) Whenever comparison
of the test product and the reference material is to be based on blood
concentration-time curves at steady-state, sufficient samples of blood
should be taken to define adequately the predose blood concentration on
3 or more consecutive days to establish that steady-state conditions
are achieved.
(2) Whenever comparison of the test product and the reference
material is to be based on cumulative urinary excretion-time curves at
steady-state, sufficient samples of urine should be taken to define the
rate and extent of
[[Page 64228]]
urinary excretion on 3 or more consecutive days to establish that
steady-state conditions are achieved.
* * * * *
(e) * * *
(3) Other methods based on valid scientific reasons should be used
to determine the bioavailability or bioequivalence of a drug product
having dose-dependent kinetics (nonlinear system).
* * * * *
13. Section 320.29 is amended by revising the section heading and
paragraph (a) to read as follows:
Sec. 320.29 Analytical methods for an vivo bioavailability or
bioequivalence study.
(a) The analytical method used in an in vivo bioavailability or
bioequivalence study to measure the concentration of the active drug
ingredient or therapeutic moiety, or its metabolite(s), in body fluids
or excretory products, or the method used to measure an acute
pharmacological effect shall be demonstrated to be accurate and of
sufficient sensitivity to measure, with appropriate precision, the
actual concentration of the active drug ingredient or therapeutic
moiety, or its metabolite(s), achieved in the body.
* * * * *
14. Section 320.30 is amended by revising paragraph (c) to read as
follows:
Sec. 320.30 Inquiries regarding bioavailability and bioequivalence
requirements and review of protocols by the Food and Drug
Administration.
* * * * *
(c)(1) General inquiries relating to in vivo bioavailability
requirements and methodology shall be submitted to the Food and Drug
Administration, Center for Drug Evaluation and Research, Office of
Clinical Pharmacology and Biopharmaceutics (HFD-850), 5600 Fishers
Lane, Rockville, MD 20857.
(2) General inquiries relating to bioequivalence requirements and
methodology shall be submitted to the Food and Drug Administration,
Center for Drug Evaluation and Research, Division of Bioequivalence
(HFD-650), 7500 Standish Pl., Rockville, MD 20855-2773.
Sec. 320.31 [Amended]
15. Section 320.31 Applicability of requirements regarding an
``Investigational New Drug Application is amended in the introductory
text of paragraph (b) by adding after the word ``bioavailability'' the
phrase ``or bioequivalence''.
Dated: November 5, 1998.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 98-30880 Filed 11-18-98; 8:45 am]
BILLING CODE 4160-01-F