[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