[Federal Register Volume 67, Number 244 (Thursday, December 19, 2002)]
[Rules and Regulations]
[Pages 77668-77675]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-31996]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 320

[Docket No. 98N-0778]
RIN 0910-AC47


Bioavailability and Bioequivalence Requirements; Abbreviated 
Applications; Final Rule

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Final rule.

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SUMMARY:  The Food and Drug Administration (FDA) is amending 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:  This rule is effective February 18, 2003.

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) to provide information pertaining to bioavailability and 
bioequivalence (Sec.  314.94(a)(7) (21 CFR 314.94(a)(7)).
    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 (Public Law 98-417).
    In the Federal Register of November 19, 1998 (63 FR 64222), FDA 
proposed to revise its regulations on bioavailability and 
bioequivalence and the content and format of an ANDA to reflect current 
FDA policy and to correct certain typographical and inadvertent errors 
(the proposed rule). The publication of this final rule completes this 
rulemaking.

II. Description of the Final Rule

    FDA is finalizing the proposed rule with the following revisions 
made in response to comments received on the proposal.
    As proposed, the final rule changes the term ``enteric coated'' to 
``delayed release'' and the term ``controlled release'' to ``extended 
release'' in Sec.  320.22(c). To conform to this change, the final rule 
also amends Sec. Sec.  320.1, 320.22(d)(2)(iv), 320.25(f), 
320.27(a)(3)(iv), 320.27(b)(2), 320.28, and 320.31 by changing 
``controlled release'' to ``extended release.'' To conform to the new 
terminology, the final rule also amends Sec.  320.25(f) by changing 
``noncontrolled release'' to ``nonextended release.''
    The following new first sentence has been added to redesignated 
Sec.  320.25(a)(2): ``An in vivo bioavailability study is generally 
done in a normal adult population under standardized conditions.'' This 
sentence is a necessary lead-in for the existing text that refers to 
situations in which

[[Page 77669]]

bioavailability studies may be conducted in patients.
    The proposed rule would have revised Sec.  320.26(b)(2)(i) to 
require a customary drug elimination period of five times, rather than 
at least three times, the half-life of the active drug ingredient or 
therapeutic moiety, or its active metabolite(s). In response to a 
comment pointing out that a drug elimination period of five half-lives 
may be impractically long for a drug with a long half-life, the agency 
has decided not to revise Sec.  320.26(b)(2)(i).
    The proposed rule would have revised Sec.  320.27(d)(1) and (d)(2) 
to state that blood or urine samples should be taken on 3 or more 
consecutive days to establish that steady-state conditions have been 
achieved. Some comments stated that obtaining samples on consecutive 
days may be impractical and, for drugs with long half-lives, may be 
less sensitive to the establishment of steady state than data obtained 
over a longer period of time. The final rule requires that 
``appropriate dosage administration and sampling should be carried out 
to document steady state.'' Specific advice about dosage administration 
and sampling may be obtained from the appropriate review division for 
the drug product.

III. Comments on the Proposed Rule

    The agency received seven comments from pharmaceutical companies, 
pharmaceutical company trade associations, and a law firm.

A. Inactive Ingredients

    Section 314.94(a)(9) establishes information requirements for the 
chemistry, manufacturing, and controls section of an abbreviated 
application. Section 314.94(a)(9)(ii) through (v) 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 agency proposed to amend 
this section to recognize the possibility that the use of different 
inactive ingredients can also affect a product's efficacy.
    (Comment 1) We received several comments about the addition of the 
word ``efficacy.'' One comment said this change is unnecessary because 
demonstrating bioequivalence provides proof of efficacy. One comment 
interpreted the change as suggesting that FDA is departing from its 
position that bioequivalence shows that the generic product is as 
effective as its reference listed drug. This comment asked what 
additional proof of effectiveness FDA would require. One comment agreed 
with the proposed change and asked that it apply to pending ANDA's. 
This comment also stated that animal tests should not be used to 
demonstrate that different inactive ingredients do not affect safety or 
efficacy because the act prohibits the use of animal or clinical 
studies to establish that the drug is safe or effective. Another 
comment expressed concern that the need to show that a different 
inactive ingredient does not affect safety or efficacy makes it more 
difficult to get approval for a generic topical drug product because 
clinical trials must be conducted.
    As stated in the proposed rule, by adding the word ``efficacy,'' 
the agency acknowledges the possibility that the use of different 
inactive ingredients can also affect a product's efficacy. FDA is not 
departing from its position that a generic product that demonstrates 
bioequivalence to the reference listed drug has shown that it is as 
effective as that reference listed drug.
    The agency disagrees with the comment stating the animal tests 
should not be used in the process of assessing the safety or efficacy 
of inactive ingredients that differ from those in the reference listed 
drug. In the preamble to the proposed ANDA regulations, the agency 
suggested that data from animal studies might be used as limited 
confirmatory testing to support an ANDA suitability petition or an ANDA 
resulting from such a petition (54 FR 28872 at 28880, July 10, 1989). 
The preamble cited as an example the use of limited confirmatory 
testing to show that an approved change in an active ingredient did not 
have acute effects on the safety of the product. In similar fashion, 
animal studies may be useful and appropriate to assist FDA in 
evaluating the safety or the effect on efficacy of a changed inactive 
ingredient.
    Section 314.127 (21 CFR 314.127) lists the reasons why FDA will 
refuse to approve an ANDA. The agency proposed to 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.
    (Comment 2) One comment stated that the proposed change is 
consistent with FDA's current policy when applied to parenteral and 
ophthalmic dosage forms, but otherwise is inconsistent with current 
policy. Another comment said this change is unnecessary because 
demonstrating bioequivalence provides proof of efficacy.
    As stated in the proposed rule, and in the response to the previous 
comment, the addition of the word ``efficacy'' simply clarifies the 
current FDA approach rather than effecting a substantive change.

B. Pharmaceutical Equivalents

    Proposed Sec.  320.1(c) revised the definition of ``pharmaceutical 
equivalents'' with regard to drug products that contain a reservoir 
that facilitates delivery or where residual volume may vary.
    (Comment 3) One comment approved of the change. The final rule is 
unchanged from the proposed rule.

C. Manufacturing Site Change

    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 
agency proposed to 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.
    (Comment 4) Several comments asserted that this proposed change is 
inconsistent with FDA's guidance ``Immediate Release Solid Oral Dosage 
Forms--Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and 
Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence 
Documentation'' (November 1995) (SUPAC-IR guidance), which does not 
specify a demonstration of bioequivalence for level 1-3 changes. The 
comments recommended that any change to the regulation be consistent 
with the SUPAC-IR guidance.
    FDA believes that this change is consistent with the SUPAC-IR 
guidance. The SUPAC-IR guidance describes the levels of changes, 
recommended tests, and filing documentation that ensure continuing 
product quality and performance characteristics of an immediate release 
dosage form for specific postapproval changes. Depending on the level 
of change and the solubility and permeability characteristics of the 
active drug substance, the SUPAC-IR guidance recommends different 
levels of in vitro dissolution tests and/or in vivo bioequivalence 
studies. The addition of a change in the manufacturing site to

[[Page 77670]]

Sec.  320.21(c)(1) does not mean that the agency would require an in 
vivo demonstration of bioequivalence in the circumstances provided for 
in the SUPAC-IR guidance. For manufacturing site changes, dissolution 
testing alone is generally sufficient to ensure unchanged product 
quality and performance for an immediate release solid oral dosage 
form. FDA expects to continue to follow the SUPAC-IR guidance in 
implementing Sec.  320.21(c)(1) as revised.

D. Delayed Release and Extended Release Terminology

    The agency proposed to amend Sec.  320.22(c) to change ``enteric 
coated'' to ``delayed release'' and ``controlled release'' to 
``extended release.''
    (Comment 5) One comment stated that these terms should also be 
replaced in Sec.  320.22(d)(2)(iv).
    FDA agrees with this comment. The final rule amends Sec.  
320.22(d)(2)(iv) by changing ``enteric coated'' to ``delayed release'' 
and ``controlled release'' to ``extended release.'' The final rule also 
amends Sec. Sec.  320.1, 320.25(f), 320.27(a)(3)(iv), 320.27(b)(2), 
320.28, and 320.31 by changing ``controlled release'' to ``extended 
release.'' To conform to these changes, the final rule also amends 
Sec.  320.25(f) by changing ``noncontrolled release'' to ``nonextended 
release.''

E. Bioavailability Is Measured

    Section 320.24 describes the types of evidence needed to establish 
bioavailability or bioequivalence. Instead of stating that 
bioavailability is demonstrated or established, the agency proposed to 
use the word ``measured.''
    (Comment 6) One comment objected to this across-the-board change, 
asserting that it is not possible to get a quantitative measure of 
bioavailability from an acute pharmacological effect, a well-controlled 
clinical trial, or an in vitro test. The comment suggested that the 
words ``demonstrated'' or ``established'' be used in discussing these 
types of evidence.
    FDA disagrees with this comment. Bioavailability is an 
observational measure that always results in a quantitative figure. 
Therefore, the final rule will remain as it was proposed.

F. Subjects for Bioavailability Studies

    The agency proposed to remove Sec.  320.25(a)(2) and redesignate 
Sec.  320.25(a)(3) as Sec.  320.25(a)(2). Current Sec.  320.25(a)(2) 
provides in part 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.''
    (Comment 7) One comment proposed the following new first sentence 
for redesignated Sec.  320.25(a)(2): ``An in vivo bioavailability study 
shall ordinarily be done in normal adults under standardized 
conditions.'' The comment stated that this sentence is a necessary 
lead-in for the existing text that refers to situations in which 
bioavailability studies may be conducted in patients.
    FDA agrees with this comment and has included similar language in 
the final rule.

G. Drug Elimination Period

    Proposed Sec.  320.26(b)(2)(i) stated that the customary drug 
elimination period should be five times the half-life of the active 
drug ingredient or therapeutic moiety, or its active metabolite(s).
    (Comment 8) FDA received several comments on this section. One 
comment approved of the change from the three half-lives in the current 
regulation, while another comment recommended four half-lives. One 
comment disagreed with using half-life multiples to establish the 
duration of sampling because the terminal half-life is a function of 
the study design and the sensitivity of the assay and, in many cases, 
represents the elimination of small amounts of drug from deep 
compartments. In those cases, a five half-life requirement may greatly 
overestimate the time needed to measure the area under the curve (AUC) 
extrapolated to infinity. The comment recommended that the rule state: 
``The duration of blood sampling should be adequate to insure that the 
measured AUC represents at least 90% of AUC (infinity)'' (AUC[infin]). 
Another comment, noting that many drugs exhibit multiexponential serum 
concentration-time profiles, asked FDA to substitute ``97% of the 
AUC[infin]'' for ``five times the half-life.''
    The agency recognizes that for a drug with a long half-life, a drug 
elimination period of five half-lives may be impractically long. FDA 
has concluded that a drug elimination period of three half-lives, which 
characterizes approximately 88 percent of the AUC[infin], is sufficent. 
Therefore, the final rule leaves Sec.  320.26(b)(2)(i) unchanged.
    (Comment 9) One comment suggested that Sec.  320.26(b)(2) should 
use an alternative phrase such as ``washout period'' or ``time between 
dosings'' rather than the term ``drug elimination period'' because that 
term could be confused with the concept of drug elimination. FDA 
disagrees with this comment. The term ``drug elimination period'' has 
been used in Sec.  320.26(b)(2) since the bioequivalence regulations 
were finalized in 1992, and the agency has not found that it causes 
confusion. Drug elimination is the metabolic process that eliminates 
the drug from the body. The drug elimination period is the time allowed 
for subjects to clear the first drug from the body before giving the 
second drug. The term ``drug elimination period'' is retained in the 
final rule.

H. Sampling to Establish Steady State

    Proposed Sec.  320.27(d)(1) and (d)(2) would have required sampling 
on 3 or more consecutive days to establish that steady-state conditions 
have been achieved whenever comparison of the test product and the 
reference material is to be based on blood concentration-time curves at 
steady state or urinary excretion-time curves at steady state.
    (Comment 10) Several comments suggested deleting the word 
``consecutive'' from Sec.  320.27(d)(1). One comment stated that drugs 
with long half-lives accumulate slowly and the use of data from 
consecutive days for such drugs is less sensitive to the establishment 
of steady state than data obtained over a longer period of time. 
Another comment said that the 3-consecutive-day requirement is often 
not practical, particularly for urinary collection, and proposed dosing 
drugs for five to six half-lives or 1 week, whichever is longer, and 
then sampling blood or urine over one dosing interval.
    One comment agreed that it is appropriate to obtain samples on 3 or 
more consecutive days. This comment stated that sometimes predose blood 
concentrations may be below the limit of quantitation; then it would 
not be possible to confirm attainment of steady state. The comment 
recommended that the predose collection time should be at a time when 
the blood drug concentrations are in the reliable range of quantitation 
of the assay and will be identical on all 3 days for all subjects.
    Another comment stated that the proposed change to Sec.  
320.27(d)(1) reflects current practice, but that the requirement for 
consecutive-day data in Sec.  320.27(d)(2) is unnecessarily 
restrictive. This comment proposed eliminating the word ``consecutive'' 
and instead saying ``to define adequately the predose blood 
concentration on 3 or more days (or doses) to establish that steady-
state conditions are achieved.''
    The agency has carefully considered these comments and has decided 
not to require that sampling be done on 3 or more consecutive days. 
Therefore, FDA has revised Sec.  320.27(d)(1) and (d)(2) to state that 
``* * * appropriate dosage administration and sampling should be 
carried out to document attainment of steady state.''

[[Page 77671]]

    Current Sec.  320.27(d)(1) requires that blood sampling be 
sufficient to define both the minimum (Cmin) and maximum (Cmax) blood 
concentrations on 2 or more consecutive days to establish that steady-
state conditions have been achieved. The preamble to the proposed rule 
explained that one of the reasons the agency proposed to revise Sec.  
320.27(d)(1) is that FDA no longer uses Cmax values to determine 
steady-state conditions. The proposed rule also stated that, in some 
cases, the predose trough level may not be the observed Cmin value.
    (Comment 11) One comment stated that the agency's proposal to 
revise Sec.  320.27(d)(1) appeared contradictory because it would 
require that trough samples be measurable in order to establish steady 
state. The comment stated: ``The Agency should address these drugs (or 
drug products) which have a relatively short half-life (relative to the 
pharmacodynamic effect and dosing interval). Is it still acceptable to 
measure only trough values when the concentrations are less than the 
analytical lower limit of quantitation?''
    As discussed in the response to comment 10, the agency is not 
revising Sec.  320.27(d)(1) as set forth in the proposed rule. Instead, 
the final rule revises Sec.  320.27(d)(1) to state that ``* * * 
appropriate dosage administration and sampling should be carried out to 
document attainment of steady state.'' This revision will permit the 
sampling schedule used to document steady state to be tailored to the 
characteristics of the drug being studied. Specific questions about the 
appropriateness and design of multiple-dose studies should be directed 
to the appropriate review division in the Office of New Drugs or to the 
Office of Generic Drugs.

I. Addition of Bioequivalence

    The proposed rule added the words ``or bioequivalence'' after the 
word ``bioavailability'' in the section heading of Sec.  320.27 and 
throughout the section.
    (Comment 12) One comment pointed out that the preamble to the 
proposed rule did not discuss the addition of the words ``or 
bioequivalence'' to Sec.  320.27(e)(3). The comment has caused the 
agency to reconsider its proposal to amend Sec.  320.27 to apply to 
bioequivalence as well as bioavailability. Section 320.27 discusses 
circumstances in which multiple-dose studies may be needed. FDA's 
current scientific thinking is that single-dose pharmacokinetic studies 
are preferable to multiple-dose studies to demonstrate bioequivalence 
because they are generally more sensitive in assessing release of the 
drug substance from the drug product into the systemic circulation. 
Accordingly, the agency has decided not to add the words ``or 
bioequivalence'' to Sec.  320.27.

J. Additional Definitions

    Proposed Sec.  320.29(a) added the words ``or bioequivalence'' 
after the word ``bioavailability'' to the discussion of the analytical 
method used in an in vivo study.
    (Comment 13) One comment asked FDA to revise Sec.  320.29(a) to 
include several definitions. The comment suggested that ``active'' 
metabolite should be defined because the concept is vague and many 
metabolites that are present in low concentrations may not contribute 
to the overall activity of the drug. In addition, the comment stated 
that FDA should define active metabolites with respect to their 
activity relative to the parent drug and relative concentration. This 
comment also asked FDA to define the ``sufficient sensitivity'' that is 
required to measure the active drug and/or metabolites. The comment 
said that it is reasonable to expect laboratories to provide a 
calibration range that provides a 32-fold range (5 half-lives) from the 
mean Cmax to the lower limit of quantitation, and this range is more 
than adequate to define more than 95 percent of the plasma AUC.
    FDA declines to add definitions of these concepts to Sec.  
320.29(a). Ascertaining the active metabolite can be a complex matter 
that requires a case-by-case approach rather than a regulatory 
definition. In October 2000, the agency published a guidance entitled 
``Bioavailability and Bioequivalence Studies for Orally Administered 
Drug Products--General Considerations'' that discusses moieties that 
should be measured in bioavailability and bioequivalence studies.

K. Miscellaneous Changes

    The final rule replaces the period at the end of Sec.  
320.22(b)(3)(i) with a semicolon and the word ``and''.
    The proposed rule added to Sec.  320.22(b)(3)(i) the language ``a 
solution for aerosolization or nebulization, a nasal solution.'' To 
conform to this change, the final rule adds language to Sec.  
320.22(b)(3)(iii) to indicate that products intended to act locally 
such as a solution for aerosolization or nebulization or a nasal 
solution should not contain an 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 systemic or local availability.
    The proposed rule added the word ``active'' before the word 
``metabolite(s)'' in Sec.  320.27(b)(3)(i). To conform to this 
addition, the final rule amends Sec.  320.29 to add the word ``active'' 
before the word ``metabolite(s).''

IV. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) through (k) 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.

V. Analysis of Impacts

    FDA has examined the impacts of the final 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; distributive impacts; and equity). The agency believes that 
this final rule is consistent with the regulatory philosophy and 
principles identified in the Executive order. The final rule amends the 
bioavailability and bioequivalence regulations to reflect current FDA 
policy. Thus, the final rule is not a significant action as defined by 
the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options to minimize any significant impact on a substantial 
number of small entities. The agency certifies that the final rule 
would not have a significant impact on a substantial number of small 
entities because the final rule merely amends the bioavailability and 
bioequivalence regulations to reflect current FDA practice. Therefore, 
under the Regulatory Flexibility Act, no further analysis is required.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 (Public 
Law 104-4) requires that agencies prepare a written statement of 
anticipated costs and benefits before proposing any rule that may 
result in an expenditure by State, local, and tribal governments, in 
the aggregate, or by the private sector, of $100 million or more in any 
one year (adjusted annually for inflation). The Unfunded Mandates 
Reform Act does not require FDA to prepare a statement of costs and 
benefits for the final rule because the rule is not

[[Page 77672]]

expected to result in any 1-year expenditure that would exceed $100 
million adjusted for inflation. The current inflation-adjusted 
statutory threshold is $110 million.

VI. Paperwork Reduction Act of 1995

    FDA concludes that this final rule does not require information 
collections subject to review by the Office of Management and Budget 
(OMB) under the Paperwork Reduction Act of 1995 (Public Law 104-13).

VII. Executive Order 13132: Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between National Government and the States, 
or on the distribution of power and responsibilities among the various 
levels of government. Accordingly, the agency has concluded that the 
rule does not contain policies that have federalism implications as 
defined in the Executive order and, consequently, a federalism summary 
impact statement is not required.

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, 21 CFR parts 
314 and 320 are amended as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW 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, 355a, 356, 
356a, 356b, 356c, 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 the phrase 
``or efficacy'' after the word ``safety'' 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 paragraph (a)(8)(ii)(A) introductory text and 
in paragraphs (a)(8)(ii)(B) and (a)(8)(ii)(C) by adding the phrase ``or 
efficacy'' after the word ``safety'' each time it appears.

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, 371.
    5. Section 320.1 is amended in paragraph (e) by removing the word 
``controlled'' and adding in its place the word ``extended'' and 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:
    a. Removing paragraph (d)(1);
    b. Redesignating paragraphs (d)(2) and (d)(3) as paragraphs (d)(1) 
and (d)(2), respectively;
    c. Revising newly redesignated paragraphs (d)(2)(i) and (d)(2)(ii); 
and
    d. Revising paragraphs (a)(1), (a)(2), (b)(1), (b)(2), (c)(1), (e), 
and (f), paragraph (g) introductory text, and paragraphs (g)(2) and 
(h).
    The revisions 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 the manufacturing site or 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

[[Page 77673]]

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) introductory text, paragraphs (b)(1)(ii), 
(b)(2)(ii), (b)(3)(i), (b)(3)(ii), (b)(3)(iii), and (c), paragraph (d) 
introductory text, paragraphs (d)(2)(i), (d)(2)(iv), 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; and
    (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 for products that are systemically absorbed, or that may 
significantly affect systemic or local availability for products 
intended to act locally.
    (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 
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;
* * * * *
    (iv) Paragraph (d) of this section does not apply to delayed 
release or extended release products.
* * * * *
    (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:
    a. Revising the section heading and the first, second, and last 
sentences of paragraph (a);
    b. Removing paragraph (b)(1)(iii); and
    c. Revising the first, second, and last sentences of paragraph 
(b)(4), paragraphs (b)(5) and (b)(6), and paragraph (c) introductory 
text.
    The revisions 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

[[Page 77674]]

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:
    a. Removing paragraph (a)(2);
    b. Redesignating paragraph (a)(3) as paragraph (a)(2);
    c. Revising newly redesignated paragraph (a)(2), paragraph (d)(1), 
paragraph (e)(1) introductory text, and paragraph (e)(1)(i);
    d. Revising the heading of paragraph (f) to read ``Extended release 
formulations.'';
    e. Removing from paragraph (f) the word ``controlled'' each time it 
appears and adding in its place the word ``extended''; and
    f. Removing from paragraph (f)(iii) the word ``noncontrolled'' and 
adding in its place the word ``nonextended''.
    The revisions read as follows:


Sec.  320.25   Guidelines for the conduct of an in vivo bioavailability 
study.

    (a) * * *
    (2) An in vivo bioavailability study is generally done in a normal 
adult population under standardized conditions. In some situations, an 
in vivo bioavailability study in humans may preferably and more 
properly be done in suitable patients. Critically ill patients shall 
not be included in an in vivo bioavailability study unless the 
attending physician determines that there is a potential benefit to the 
patient.
* * * * *
    (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 
paragraph (a)(1) 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.
* * * * *
    12. Section 320.27 is amended by:
    a. Revising paragraphs (a)(3)(iv), (d)(1), and (d)(2);
    b. Removing from paragraph (b)(2) the word ``controlled'' and 
adding in its place the word ``extended''; and
    c. Adding in paragraph (b)(3)(i) the word ``active'' before the 
word ``metabolite(s),''.
    The additions and revisions read as follows:


Sec.  320.27   Guidelines on the design of a multiple-dose in vivo 
bioavailability study.

    (a) * * *
    (3) * * *
    (iv) The drug product is an extended release dosage form.
* * * * *
    (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, appropriate dosage 
administration and sampling should be carried out to document 
attainment of steady state.
    (2) Whenever comparison of the test product and the reference 
material is to be based on cumulative urinary excretion-time curves at 
steady state, appropriate dosage administration and sampling should be 
carried out to document attainment of steady state.
* * * * *


Sec.  320.28   [Amended]

    13. Section 320.28 Correlation of bioavailability with an acute 
pharmacological effect or clinical evidence is amended by removing the 
word ``controlled'' and adding in its place the word ``extended''.
    14. Section 320.29 is amended by revising the section heading and 
paragraph (a) and by adding the word ``active'' before the word 
``metabolite(s)'' in paragraph (b) to read as follows:


Sec.  320.29   Analytical methods for an in 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 active 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 active metabolite(s), achieved in the body.
* * * * *
    15. 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]

    16. Section 320.31 Applicability of requirements regarding an 
``Investigational New Drug Application'' is amended in paragraph (b) 
introductory text by adding after the word ``bioavailability'' the 
phrase ``or bioequivalence'' and in paragraph (b)(3) by removing the 
word ``controlled'' and adding in its place the word ``extended''.


[[Page 77675]]


    Dated: December 8, 2002.
Margaret M. Dotzel,
Assistant Commissioner for Policy.
[FR Doc. 02-31996 Filed 12-18-02; 8:45 am]
BILLING CODE 4160-01-S