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77668 Federal Register / Vol. 67, No.

244 / Thursday, December 19, 2002 / Rules and Regulations

(ii) One or more construction (1) The agency or a construction Evaluation and Research (HFD–7), Food
contracts (includes any contract manager acting on behalf of the and Drug Administration, 5600 Fishers
awarded by the recipient) subject to Government had issued or was party to Lane, Rockville, MD 20857, 301–594–
such requirements or prohibitions had bid specifications, project agreements, 2041.
been awarded. agreements with one or more labor SUPPLEMENTARY INFORMATION:
(4) The Assistant Administrator for organizations, or other controlling
Procurement may exempt a particular documents with respect to that I. Background
project, contract, or subcontract from particular project, which contained any FDA regulations require persons
this policy upon a finding that special of the requirements or prohibitions in submitting a new drug application
circumstances require an exemption in paragraph (d)(1) of this section; and (NDA) to provide bioavailability
order to avert an imminent threat to (2) One or more construction information (21 CFR 314.50(c)(2)(vi) and
public health or safety, or to serve the contracts (includes any contract (d)(3)), and persons submitting an
national security. A finding of ‘‘special awarded by the recipient) subject to abbreviated new drug application
circumstances’’ may not be based on the such requirements or prohibitions had (ANDA) to provide information
possibility or presence of a labor dispute been awarded. pertaining to bioavailability and
concerning the use of contractors or (d) The Assistant Administrator for bioequivalence (§ 314.94(a)(7) (21 CFR
subcontractors who are nonsignatories Procurement may exempt a particular 314.94(a)(7)).
to, or otherwise do not adhere to, project, contract, or subcontract from FDA regulations in part 320 (21 CFR
agreements with one or more labor this policy upon a finding that special part 320) establish definitions and
organizations, or concerning employees circumstances require an exemption in requirements for bioavailability and
on the project who are not members of, order to avert an imminent threat to bioequivalence studies. FDA finalized
or affiliated with, a labor organization. public health or safety, or to serve the the bioavailability and bioequivalence
national security. A finding of ‘‘special regulations on January 7, 1977 (42 FR
PART 1274—COOPERATIVE circumstances’’ may not be based on the 1624), and amended these regulations
AGREEMENTS WITH COMMERCIAL possibility or presence of a labor dispute on April 28, 1992 (57 FR 17950). The
FIRMS concerning the use of contractors or 1992 amendments were designed to
subcontractors who are nonsignatories reflect statutory changes resulting from
3. The authority citation for part 1274 to, or otherwise do not adhere to,
continues to read as follows: the Drug Price Competition and Patent
agreements with one or more labor Term Restoration Act of 1984 (Public
Authority: 31 U.S.C. 6301 to 6308; 42 organizations, or concerning employees Law 98–417).
U.S.C. 2451 et seq. on the project who are not members of, In the Federal Register of November
4. 1274.215 is added to read as or affiliated with, a labor organization. 19, 1998 (63 FR 64222), FDA proposed
follows: [FR Doc. 02–31682 Filed 12–18–02; 8:45 am] to revise its regulations on
BILLING CODE 7510–01–P bioavailability and bioequivalence and
§ 1274.215 Federal and federally funded
construction projects.
the content and format of an ANDA to
reflect current FDA policy and to correct
(a) In accordance with E.O. 13202 of certain typographical and inadvertent
February 17, 2001, ‘‘Preservation of DEPARTMENT OF HEALTH AND
HUMAN SERVICES errors (the proposed rule). The
Open Competition and Government publication of this final rule completes
Neutrality Towards Government this rulemaking.
Food and Drug Administration
Contractors’ Labor Relations on Federal
and Federally Funded Construction II. Description of the Final Rule
21 CFR Parts 314 and 320
Projects’’, as amended on April 6, 2001, FDA is finalizing the proposed rule
the Government, or any construction [Docket No. 98N–0778] with the following revisions made in
manager acting on behalf of the response to comments received on the
RIN 0910–AC47
Government, shall not— proposal.
(1) Require or prohibit recipients, Bioavailability and Bioequivalence As proposed, the final rule changes
potential recipients or subrecipients to Requirements; Abbreviated the term ‘‘enteric coated’’ to ‘‘delayed
enter into or adhere to agreements with Applications; Final Rule release’’ and the term ‘‘controlled
one or more labor organizations (as release’’ to ‘‘extended release’’ in
defined in 42 U.S.C. 2000e(d)) on the AGENCY: Food and Drug Administration, § 320.22(c). To conform to this change,
same or other related construction HHS. the final rule also amends §§ 320.1,
projects; or ACTION: Final rule. 320.22(d)(2)(iv), 320.25(f),
(2) Otherwise discriminate against 320.27(a)(3)(iv), 320.27(b)(2), 320.28,
recipients, potential recipients or SUMMARY: The Food and Drug
and 320.31 by changing ‘‘controlled
subrecipients for becoming, refusing to Administration (FDA) is amending its release’’ to ‘‘extended release.’’ To
become, or remaining signatories or regulations on bioavailability and conform to the new terminology, the
otherwise adhering to agreements with bioequivalence and on the content and final rule also amends § 320.25(f) by
one or more organizations, on the same format of an abbreviated application to changing ‘‘noncontrolled release’’ to
or other related construction projects. reflect current FDA policy and to correct ‘‘nonextended release.’’
(b) Nothing in this section prohibits certain typographical and inadvertent The following new first sentence has
the recipient, potential recipients or errors. This action is intended to been added to redesignated
subrecipients from voluntarily entering improve the accuracy and clarity of the § 320.25(a)(2): ‘‘An in vivo
into project labor agreements. regulations. bioavailability study is generally done
(c) The Assistant Administrator for DATES: This rule is effective February in a normal adult population under
Procurement may exempt a construction 18, 2003. standardized conditions.’’ This sentence
project from this policy if, as of FOR FURTHER INFORMATION CONTACT: is a necessary lead-in for the existing
February 17, 2001— Christine F. Rogers, Center for Drug text that refers to situations in which

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Federal Register / Vol. 67, No. 244 / Thursday, December 19, 2002 / Rules and Regulations 77669

bioavailability studies may be listed drug. This comment asked what As stated in the proposed rule, and in
conducted in patients. additional proof of effectiveness FDA the response to the previous comment,
The proposed rule would have would require. One comment agreed the addition of the word ‘‘efficacy’’
revised § 320.26(b)(2)(i) to require a with the proposed change and asked simply clarifies the current FDA
customary drug elimination period of that it apply to pending ANDA’s. This approach rather than effecting a
five times, rather than at least three comment also stated that animal tests substantive change.
times, the half-life of the active drug should not be used to demonstrate that
ingredient or therapeutic moiety, or its B. Pharmaceutical Equivalents
different inactive ingredients do not
active metabolite(s). In response to a affect safety or efficacy because the act Proposed § 320.1(c) revised the
comment pointing out that a drug prohibits the use of animal or clinical definition of ‘‘pharmaceutical
elimination period of five half-lives may studies to establish that the drug is safe equivalents’’ with regard to drug
be impractically long for a drug with a or effective. Another comment products that contain a reservoir that
long half-life, the agency has decided expressed concern that the need to show facilitates delivery or where residual
not to revise § 320.26(b)(2)(i). that a different inactive ingredient does volume may vary.
The proposed rule would have not affect safety or efficacy makes it (Comment 3) One comment approved
revised § 320.27(d)(1) and (d)(2) to state more difficult to get approval for a of the change. The final rule is
that blood or urine samples should be generic topical drug product because unchanged from the proposed rule.
taken on 3 or more consecutive days to clinical trials must be conducted. C. Manufacturing Site Change
establish that steady-state conditions As stated in the proposed rule, by
have been achieved. Some comments Section 320.21(c)(1) provides that any
adding the word ‘‘efficacy,’’ the agency person submitting a supplemental
stated that obtaining samples on acknowledges the possibility that the
consecutive days may be impractical application to FDA must provide
use of different inactive ingredients can evidence or information regarding the
and, for drugs with long half-lives, may also affect a product’s efficacy. FDA is
be less sensitive to the establishment of product’s bioavailability or
not departing from its position that a bioequivalence if the supplemental
steady state than data obtained over a generic product that demonstrates
longer period of time. The final rule application proposes ‘‘[a] change in the
bioequivalence to the reference listed manufacturing process, including a
requires that ‘‘appropriate dosage drug has shown that it is as effective as
administration and sampling should be change in product formulation or dosage
that reference listed drug. strength, beyond the variations provided
carried out to document steady state.’’ The agency disagrees with the
Specific advice about dosage for in the approved application.’’ The
comment stating the animal tests should agency proposed to amend this
administration and sampling may be not be used in the process of assessing
obtained from the appropriate review provision to include a change in the
the safety or efficacy of inactive manufacturing site because such a
division for the drug product. ingredients that differ from those in the change may affect the bioavailability or
III. Comments on the Proposed Rule reference listed drug. In the preamble to bioequivalence of the drug product
The agency received seven comments the proposed ANDA regulations, the because of equipment, personnel, or
from pharmaceutical companies, agency suggested that data from animal environmental changes.
pharmaceutical company trade studies might be used as limited (Comment 4) Several comments
associations, and a law firm. confirmatory testing to support an asserted that this proposed change is
ANDA suitability petition or an ANDA inconsistent with FDA’s guidance
A. Inactive Ingredients resulting from such a petition (54 FR ‘‘Immediate Release Solid Oral Dosage
Section 314.94(a)(9) establishes 28872 at 28880, July 10, 1989). The Forms—Scale-Up and Post-Approval
information requirements for the preamble cited as an example the use of Changes: Chemistry, Manufacturing and
chemistry, manufacturing, and controls limited confirmatory testing to show Controls; In Vitro Dissolution Testing
section of an abbreviated application. that an approved change in an active and In Vivo Bioequivalence
Section 314.94(a)(9)(ii) through (v) ingredient did not have acute effects on Documentation’’ (November 1995)
provides that an abbreviated application the safety of the product. In similar (SUPAC–IR guidance), which does not
may have different inactive ingredients fashion, animal studies may be useful specify a demonstration of
than the reference listed drug as long as and appropriate to assist FDA in bioequivalence for level 1–3 changes.
the applicant identifies and evaluating the safety or the effect on The comments recommended that any
characterizes the inactive ingredients in efficacy of a changed inactive change to the regulation be consistent
the proposed drug product and provides ingredient. with the SUPAC–IR guidance.
information demonstrating that the Section 314.127 (21 CFR 314.127) lists FDA believes that this change is
inactive ingredients do not affect the the reasons why FDA will refuse to consistent with the SUPAC–IR
safety of the drug product. The agency approve an ANDA. The agency guidance. The SUPAC–IR guidance
proposed to amend this section to proposed to revise § 314.127(a)(8) to describes the levels of changes,
recognize the possibility that the use of clarify that, consistent with current FDA recommended tests, and filing
different inactive ingredients can also policy, the applicant must show that documentation that ensure continuing
affect a product’s efficacy. different inactive ingredients would not product quality and performance
(Comment 1) We received several affect a product’s efficacy. characteristics of an immediate release
comments about the addition of the (Comment 2) One comment stated dosage form for specific postapproval
word ‘‘efficacy.’’ One comment said this that the proposed change is consistent changes. Depending on the level of
change is unnecessary because with FDA’s current policy when applied change and the solubility and
demonstrating bioequivalence provides to parenteral and ophthalmic dosage permeability characteristics of the active
proof of efficacy. One comment forms, but otherwise is inconsistent drug substance, the SUPAC–IR guidance
interpreted the change as suggesting that with current policy. Another comment recommends different levels of in vitro
FDA is departing from its position that said this change is unnecessary because dissolution tests and/or in vivo
bioequivalence shows that the generic demonstrating bioequivalence provides bioequivalence studies. The addition of
product is as effective as its reference proof of efficacy. a change in the manufacturing site to

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77670 Federal Register / Vol. 67, No. 244 / Thursday, December 19, 2002 / Rules and Regulations

§ 320.21(c)(1) does not mean that the (Comment 7) One comment proposed has not found that it causes confusion.
agency would require an in vivo the following new first sentence for Drug elimination is the metabolic
demonstration of bioequivalence in the redesignated § 320.25(a)(2): ‘‘An in vivo process that eliminates the drug from
circumstances provided for in the bioavailability study shall ordinarily be the body. The drug elimination period
SUPAC–IR guidance. For manufacturing done in normal adults under is the time allowed for subjects to clear
site changes, dissolution testing alone is standardized conditions.’’ The comment the first drug from the body before
generally sufficient to ensure unchanged stated that this sentence is a necessary giving the second drug. The term ‘‘drug
product quality and performance for an lead-in for the existing text that refers to elimination period’’ is retained in the
immediate release solid oral dosage situations in which bioavailability final rule.
form. FDA expects to continue to follow studies may be conducted in patients.
FDA agrees with this comment and H. Sampling to Establish Steady State
the SUPAC–IR guidance in
implementing § 320.21(c)(1) as revised. has included similar language in the Proposed § 320.27(d)(1) and (d)(2)
final rule. would have required sampling on 3 or
D. Delayed Release and Extended more consecutive days to establish that
Release Terminology G. Drug Elimination Period steady-state conditions have been
The agency proposed to amend Proposed § 320.26(b)(2)(i) stated that achieved whenever comparison of the
§ 320.22(c) to change ‘‘enteric coated’’ to the customary drug elimination period test product and the reference material
‘‘delayed release’’ and ‘‘controlled should be five times the half-life of the is to be based on blood concentration-
release’’ to ‘‘extended release.’’ active drug ingredient or therapeutic time curves at steady state or urinary
(Comment 5) One comment stated moiety, or its active metabolite(s). excretion-time curves at steady state.
that these terms should also be replaced (Comment 8) FDA received several (Comment 10) Several comments
in § 320.22(d)(2)(iv). comments on this section. One suggested deleting the word
FDA agrees with this comment. The comment approved of the change from ‘‘consecutive’’ from § 320.27(d)(1). One
final rule amends § 320.22(d)(2)(iv) by the three half-lives in the current comment stated that drugs with long
changing ‘‘enteric coated’’ to ‘‘delayed regulation, while another comment half-lives accumulate slowly and the
release’’ and ‘‘controlled release’’ to recommended four half-lives. One use of data from consecutive days for
‘‘extended release.’’ The final rule also comment disagreed with using half-life such drugs is less sensitive to the
amends §§ 320.1, 320.25(f), multiples to establish the duration of establishment of steady state than data
320.27(a)(3)(iv), 320.27(b)(2), 320.28, sampling because the terminal half-life obtained over a longer period of time.
and 320.31 by changing ‘‘controlled is a function of the study design and the Another comment said that the 3–
release’’ to ‘‘extended release.’’ To sensitivity of the assay and, in many consecutive-day requirement is often
conform to these changes, the final rule cases, represents the elimination of not practical, particularly for urinary
also amends § 320.25(f) by changing small amounts of drug from deep collection, and proposed dosing drugs
‘‘noncontrolled release’’ to compartments. In those cases, a five for five to six half-lives or 1 week,
‘‘nonextended release.’’ half-life requirement may greatly whichever is longer, and then sampling
overestimate the time needed to blood or urine over one dosing interval.
E. Bioavailability Is Measured measure the area under the curve (AUC) One comment agreed that it is
Section 320.24 describes the types of extrapolated to infinity. The comment appropriate to obtain samples on 3 or
evidence needed to establish recommended that the rule state: ‘‘The more consecutive days. This comment
bioavailability or bioequivalence. duration of blood sampling should be stated that sometimes predose blood
Instead of stating that bioavailability is adequate to insure that the measured concentrations may be below the limit
demonstrated or established, the agency AUC represents at least 90% of AUC of quantitation; then it would not be
proposed to use the word ‘‘measured.’’ (infinity)’’ (AUC∞). Another comment, possible to confirm attainment of steady
(Comment 6) One comment objected noting that many drugs exhibit state. The comment recommended that
to this across-the-board change, multiexponential serum concentration- the predose collection time should be at
asserting that it is not possible to get a time profiles, asked FDA to substitute a time when the blood drug
quantitative measure of bioavailability ‘‘97% of the AUC∞’’ for ‘‘five times the concentrations are in the reliable range
from an acute pharmacological effect, a half-life.’’ of quantitation of the assay and will be
well-controlled clinical trial, or an in The agency recognizes that for a drug identical on all 3 days for all subjects.
vitro test. The comment suggested that with a long half-life, a drug elimination Another comment stated that the
the words ‘‘demonstrated’’ or period of five half-lives may be proposed change to § 320.27(d)(1)
‘‘established’’ be used in discussing impractically long. FDA has concluded reflects current practice, but that the
these types of evidence. that a drug elimination period of three requirement for consecutive-day data in
FDA disagrees with this comment. half-lives, which characterizes § 320.27(d)(2) is unnecessarily
Bioavailability is an observational approximately 88 percent of the AUC∞, restrictive. This comment proposed
measure that always results in a is sufficent. Therefore, the final rule eliminating the word ‘‘consecutive’’ and
quantitative figure. Therefore, the final leaves § 320.26(b)(2)(i) unchanged. instead saying ‘‘to define adequately the
rule will remain as it was proposed. (Comment 9) One comment suggested predose blood concentration on 3 or
that § 320.26(b)(2) should use an more days (or doses) to establish that
F. Subjects for Bioavailability Studies alternative phrase such as ‘‘washout steady-state conditions are achieved.’’
The agency proposed to remove period’’ or ‘‘time between dosings’’ The agency has carefully considered
§ 320.25(a)(2) and redesignate rather than the term ‘‘drug elimination these comments and has decided not to
§ 320.25(a)(3) as § 320.25(a)(2). Current period’’ because that term could be require that sampling be done on 3 or
§ 320.25(a)(2) provides in part that ‘‘[a]n confused with the concept of drug more consecutive days. Therefore, FDA
in vivo bioavailability study shall not be elimination. FDA disagrees with this has revised § 320.27(d)(1) and (d)(2) to
conducted in humans if an appropriate comment. The term ‘‘drug elimination state that ‘‘* * * appropriate dosage
animal model exists and correlation of period’’ has been used in § 320.26(b)(2) administration and sampling should be
results in animals and humans has been since the bioequivalence regulations carried out to document attainment of
demonstrated.’’ were finalized in 1992, and the agency steady state.’’

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Federal Register / Vol. 67, No. 244 / Thursday, December 19, 2002 / Rules and Regulations 77671

Current § 320.27(d)(1) requires that drug product into the systemic may significantly affect systemic or
blood sampling be sufficient to define circulation. Accordingly, the agency has local availability.
both the minimum (Cmin) and decided not to add the words ‘‘or The proposed rule added the word
maximum (Cmax) blood concentrations bioequivalence’’ to § 320.27. ‘‘active’’ before the word ‘‘metabolite(s)’’
on 2 or more consecutive days to in § 320.27(b)(3)(i). To conform to this
J. Additional Definitions addition, the final rule amends § 320.29
establish that steady-state conditions
have been achieved. The preamble to Proposed § 320.29(a) added the words to add the word ‘‘active’’ before the
the proposed rule explained that one of ‘‘or bioequivalence’’ after the word word ‘‘metabolite(s).’’
the reasons the agency proposed to ‘‘bioavailability’’ to the discussion of the IV. Environmental Impact
revise § 320.27(d)(1) is that FDA no analytical method used in an in vivo
longer uses Cmax values to determine study. The agency has determined under 21
steady-state conditions. The proposed (Comment 13) One comment asked CFR 25.30(h) through (k) that this action
rule also stated that, in some cases, the FDA to revise § 320.29(a) to include is of a type that does not individually
predose trough level may not be the several definitions. The comment or cumulatively have a significant effect
observed Cmin value. suggested that ‘‘active’’ metabolite on the human environment. Therefore,
(Comment 11) One comment stated neither an environmental assessment
should be defined because the concept
that the agency’s proposal to revise nor an environmental impact statement
is vague and many metabolites that are
§ 320.27(d)(1) appeared contradictory is required.
present in low concentrations may not
because it would require that trough contribute to the overall activity of the V. Analysis of Impacts
samples be measurable in order to drug. In addition, the comment stated
establish steady state. The comment FDA has examined the impacts of the
that FDA should define active final rule under Executive Order 12866
stated: ‘‘The Agency should address metabolites with respect to their activity
these drugs (or drug products) which and the Regulatory Flexibility Act (5
relative to the parent drug and relative U.S.C. 601–612). Executive Order 12866
have a relatively short half-life (relative concentration. This comment also asked
to the pharmacodynamic effect and directs agencies to assess all costs and
FDA to define the ‘‘sufficient benefits of available regulatory
dosing interval). Is it still acceptable to sensitivity’’ that is required to measure
measure only trough values when the alternatives and, when regulation is
the active drug and/or metabolites. The necessary, to select regulatory
concentrations are less than the comment said that it is reasonable to
analytical lower limit of quantitation?’’ approaches that maximize net benefits
expect laboratories to provide a (including potential economic,
As discussed in the response to
calibration range that provides a 32-fold environmental, public health and safety,
comment 10, the agency is not revising
range (5 half-lives) from the mean Cmax and other advantages; distributive
§ 320.27(d)(1) as set forth in the
to the lower limit of quantitation, and impacts; and equity). The agency
proposed rule. Instead, the final rule
this range is more than adequate to believes that this final rule is consistent
revises § 320.27(d)(1) to state that ‘‘* *
define more than 95 percent of the with the regulatory philosophy and
* appropriate dosage administration and
plasma AUC. principles identified in the Executive
sampling should be carried out to
document attainment of steady state.’’ FDA declines to add definitions of order. The final rule amends the
This revision will permit the sampling these concepts to § 320.29(a). bioavailability and bioequivalence
schedule used to document steady state Ascertaining the active metabolite can regulations to reflect current FDA
to be tailored to the characteristics of be a complex matter that requires a case- policy. Thus, the final rule is not a
the drug being studied. Specific by-case approach rather than a significant action as defined by the
questions about the appropriateness and regulatory definition. In October 2000, Executive order.
design of multiple-dose studies should the agency published a guidance The Regulatory Flexibility Act
be directed to the appropriate review entitled ‘‘Bioavailability and requires agencies to analyze regulatory
division in the Office of New Drugs or Bioequivalence Studies for Orally options to minimize any significant
to the Office of Generic Drugs. Administered Drug Products—General impact on a substantial number of small
Considerations’’ that discusses moieties entities. The agency certifies that the
I. Addition of Bioequivalence that should be measured in final rule would not have a significant
The proposed rule added the words bioavailability and bioequivalence impact on a substantial number of small
‘‘or bioequivalence’’ after the word studies. entities because the final rule merely
‘‘bioavailability’’ in the section heading K. Miscellaneous Changes amends the bioavailability and
of § 320.27 and throughout the section. bioequivalence regulations to reflect
(Comment 12) One comment pointed The final rule replaces the period at current FDA practice. Therefore, under
out that the preamble to the proposed the end of § 320.22(b)(3)(i) with a the Regulatory Flexibility Act, no
rule did not discuss the addition of the semicolon and the word ‘‘and’’. further analysis is required.
words ‘‘or bioequivalence’’ to The proposed rule added to Section 202(a) of the Unfunded
§ 320.27(e)(3). The comment has caused § 320.22(b)(3)(i) the language ‘‘a solution Mandates Reform Act of 1995 (Public
the agency to reconsider its proposal to for aerosolization or nebulization, a Law 104–4) requires that agencies
amend § 320.27 to apply to nasal solution.’’ To conform to this prepare a written statement of
bioequivalence as well as change, the final rule adds language to anticipated costs and benefits before
bioavailability. Section 320.27 discusses § 320.22(b)(3)(iii) to indicate that proposing any rule that may result in an
circumstances in which multiple-dose products intended to act locally such as expenditure by State, local, and tribal
studies may be needed. FDA’s current a solution for aerosolization or governments, in the aggregate, or by the
scientific thinking is that single-dose nebulization or a nasal solution should private sector, of $100 million or more
pharmacokinetic studies are preferable not contain an inactive ingredient or in any one year (adjusted annually for
to multiple-dose studies to demonstrate other change in formulation from the inflation). The Unfunded Mandates
bioequivalence because they are drug product that is the subject of the Reform Act does not require FDA to
generally more sensitive in assessing approved full new drug application or prepare a statement of costs and benefits
release of the drug substance from the abbreviated new drug application that for the final rule because the rule is not

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77672 Federal Register / Vol. 67, No. 244 / Thursday, December 19, 2002 / Rules and Regulations

expected to result in any 1-year (9) * * * b. Redesignating paragraphs (d)(2) and


expenditure that would exceed $100 (v) Inactive ingredient changes (d)(3) as paragraphs (d)(1) and (d)(2),
million adjusted for inflation. The permitted in drug products intended for respectively;
current inflation-adjusted statutory topical use. Generally, a drug product c. Revising newly redesignated
threshold is $110 million. intended for topical use, solutions for paragraphs (d)(2)(i) and (d)(2)(ii); and
aerosolization or nebulization, and nasal d. Revising paragraphs (a)(1), (a)(2),
VI. Paperwork Reduction Act of 1995 (b)(1), (b)(2), (c)(1), (e), and (f),
solutions shall contain the same
FDA concludes that this final rule inactive ingredients as the reference paragraph (g) introductory text, and
does not require information collections listed drug identified by the applicant paragraphs (g)(2) and (h).
subject to review by the Office of under paragraph (a)(3) of this section. The revisions read as follows:
Management and Budget (OMB) under However, an abbreviated application
the Paperwork Reduction Act of 1995 § 320.21 Requirements for submission of
may include different inactive in vivo bioavailability and bioequivalence
(Public Law 104–13). ingredients provided that the applicant data.
VII. Executive Order 13132: Federalism identifies and characterizes the (a) * * *
differences and provides information (1) Evidence measuring the in vivo
FDA has analyzed this final rule in
demonstrating that the differences do bioavailability of the drug product that
accordance with the principles set forth
not affect the safety or efficacy of the is the subject of the application; or
in Executive Order 13132. FDA has
proposed drug product. (2) Information to permit FDA to
determined that the rule does not
contain policies that have substantial * * * * * waive the submission of evidence
direct effects on the States, on the measuring in vivo bioavailability.
§ 314.127 [Amended] (b) * * *
relationship between National
Government and the States, or on the 3. Section 314.127 Refusal to approve (1) Evidence demonstrating that the
distribution of power and an abbreviated new drug application is drug product that is the subject of the
responsibilities among the various amended in paragraph (a)(8)(ii)(A) abbreviated new drug application is
levels of government. Accordingly, the introductory text and in paragraphs bioequivalent to the reference listed
agency has concluded that the rule does (a)(8)(ii)(B) and (a)(8)(ii)(C) by adding drug (defined in § 314.3(b) of this
not contain policies that have the phrase ‘‘or efficacy’’ after the word chapter); or
federalism implications as defined in ‘‘safety’’ each time it appears. (2) Information to show that the drug
the Executive order and, consequently, product is bioequivalent to the reference
a federalism summary impact statement
PART 320—BIOAVAILABILITY AND listed drug which would permit FDA to
is not required.
BIOEQUIVALENCE REQUIREMENTS waive the submission of evidence
demonstrating in vivo bioequivalence as
List of Subjects 4. The authority citation for 21 CFR provided in paragraph (f) of this section.
part 320 continues to read as follows: (c) * * *
21 CFR Part 314
Authority: 21 U.S.C. 321, 351, 352, 355, (1) A change in the manufacturing site
Administrative practice and 371. or a change in the manufacturing
procedure, Confidential business 5. Section 320.1 is amended in process, including a change in product
information, Drugs, Reporting and paragraph (e) by removing the word formulation or dosage strength, beyond
recordkeeping requirements. ‘‘controlled’’ and adding in its place the the variations provided for in the
21 CFR Part 320 word ‘‘extended’’ and by revising approved application.
paragraph (c) to read as follows: * * * * *
Drugs, Reporting and recordkeeping (d) * * *
requirements. § 320.1 Definitions. (2) * * *
Therefore, under the Federal Food, * * * * * (i) Evidence measuring the in vivo
Drug, and Cosmetic Act and the bioavailability and demonstrating the in
(c) Pharmaceutical equivalents means
authority delegated to the Commissioner vivo bioequivalence of the drug product
drug products in identical dosage forms
of Food and Drugs, 21 CFR parts 314 that is the subject of the application; or
that contain identical amounts of the
and 320 are amended as follows: (ii) Information to permit FDA to
identical active drug ingredient, i.e., the
same salt or ester of the same waive measurement of in vivo
PART 314—APPLICATIONS FOR FDA bioavailability.
APPROVAL TO MARKET A NEW DRUG therapeutic moiety, or, in the case of
modified release dosage forms that (e) Evidence measuring the in vivo
1. The authority citation for 21 CFR require a reservoir or overage or such bioavailability and demonstrating the in
part 314 continues to read as follows: forms as prefilled syringes where vivo bioequivalence of a drug product
residual volume may vary, that deliver shall be obtained using one of the
Authority: 21 U.S.C. 321, 331, 351, 352,
353, 355, 355a, 356, 356a, 356b, 356c, 371, identical amounts of the active drug approaches for determining
374, 379e. ingredient over the identical dosing bioavailability set forth in § 320.24.
2. Section 314.94 is amended in period; do not necessarily contain the (f) Information to permit FDA to
paragraph (a)(9)(ii) and the second same inactive ingredients; and meet the waive the submission of evidence
sentence of paragraphs (a)(9)(iii) and identical compendial or other measuring the in vivo bioavailability or
(a)(9)(iv) by adding the phrase ‘‘or applicable standard of identity, strength, demonstrating the in vivo
efficacy’’ after the word ‘‘safety’’ each quality, and purity, including potency bioequivalence shall meet the criteria
time it appears, and by revising and, where applicable, content set forth in § 320.22.
paragraph (a)(9)(v) to read as follows: uniformity, disintegration times, and/or (g) Any person holding an approved
dissolution rates. full or abbreviated new drug application
§ 314.94 Content and format of an shall submit to FDA a supplemental
abbreviated application. * * * * *
application containing new evidence
* * * * * 6. Section 320.21 is amended by: measuring the in vivo bioavailability or
(a) * * * a. Removing paragraph (d)(1); demonstrating the in vivo

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bioequivalence of the drug product that (i) Is a solution for application to the (i) The bioavailability of the other
is the subject of the application if skin, an oral solution, elixir, syrup, product has been measured; and
notified by FDA that: tincture, a solution for aerosolization or * * * * *
* * * * * nebulization, a nasal solution, or similar (e) FDA, for good cause, may waive a
(2) There are data measuring other solubilized form; and requirement for the submission of
significant intra-batch and batch-to- (ii) Contains an active drug ingredient evidence of in vivo bioavailability or
batch variability, e.g., plus or minus 25 in the same concentration and dosage bioequivalence if waiver is compatible
percent, in the bioavailability of the form as a drug product that is the with the protection of the public health.
drug product. subject of an approved full new drug ***
(h) The requirements of this section application or abbreviated new drug * * * * *
regarding the submission of evidence application; and 8. Section 320.23 is amended by
measuring the in vivo bioavailability or (iii) Contains no inactive ingredient or revising the section heading and the
demonstrating the in vivo other change in formulation from the first sentence of paragraph (a)(1) to read
bioequivalence apply only to a full or drug product that is the subject of the as follows:
abbreviated new drug application or a approved full new drug application or
supplemental application for a finished abbreviated new drug application that § 320.23 Basis for measuring in vivo
may significantly affect absorption of bioavailability or demonstrating
dosage formulation. bioequivalence.
7. Section 320.22 is amended by the active drug ingredient or active
moiety for products that are (a)(1) The in vivo bioavailability of a
revising paragraph (a), the second
systemically absorbed, or that may drug product is measured if the
sentence of paragraph (b) introductory
significantly affect systemic or local product’s rate and extent of absorption,
text, paragraphs (b)(1)(ii), (b)(2)(ii),
availability for products intended to act as determined by comparison of
(b)(3)(i), (b)(3)(ii), (b)(3)(iii), and (c),
locally. measured parameters, e.g.,
paragraph (d) introductory text,
(c) FDA shall waive the requirement concentration of the active drug
paragraphs (d)(2)(i), (d)(2)(iv), and
for the submission of evidence ingredient in the blood, urinary
(d)(4)(i), and the first sentence of
measuring the in vivo bioavailability or excretion rates, or pharmacological
paragraph (e) to read as follows:
demonstrating the in vivo effects, do not indicate a significant
§ 320.22 Criteria for waiver of evidence of bioequivalence of a solid oral dosage difference from the reference material’s
in vivo bioavailability or bioequivalence.
form (other than a delayed release or rate and extent of absorption. * * *
(a) Any person submitting a full or extended release dosage form) of a drug * * * * *
abbreviated new drug application, or a product determined to be effective for at 9. Section 320.24 is amended by:
supplemental application proposing any least one indication in a Drug Efficacy a. Revising the section heading and
of the changes set forth in § 320.21(c), Study Implementation notice or which the first, second, and last sentences of
may request FDA to waive the is identical, related, or similar to such paragraph (a);
requirement for the submission of a drug product under § 310.6 of this b. Removing paragraph (b)(1)(iii); and
evidence measuring the in vivo c. Revising the first, second, and last
chapter unless FDA has evaluated the
bioavailability or demonstrating the in sentences of paragraph (b)(4),
drug product under the criteria set forth
vivo bioequivalence of the drug product paragraphs (b)(5) and (b)(6), and
in § 320.33, included the drug product
that is the subject of the application. An paragraph (c) introductory text.
in the Approved Drug Products with The revisions read as follows:
applicant shall submit a request for Therapeutic Equivalence Evaluations
waiver with the application. Except as List, and rated the drug product as § 320.24 Types of evidence to measure
provided in paragraph (f) of this section, having a known or potential bioavailability or establish bioequivalence.
FDA shall waive the requirement for the bioequivalence problem. A drug product (a) Bioavailability may be measured or
submission of evidence of in vivo so rated reflects a determination by FDA bioequivalence may be demonstrated by
bioavailability or bioequivalence if the that an in vivo bioequivalence study is several in vivo and in vitro methods.
drug product meets any of the required. FDA may require in vivo or in vitro
provisions of paragraphs (b), (c), (d), or (d) For certain drug products, testing, or both, to measure the
(e) of this section. bioavailability may be measured or bioavailability of a drug product or
(b) * * * FDA shall waive the bioequivalence may be demonstrated by establish the bioequivalence of specific
requirement for the submission of evidence obtained in vitro in lieu of in drug products. * * * The method used
evidence obtained in vivo measuring the vivo data. FDA shall waive the must be capable of measuring
bioavailability or demonstrating the requirement for the submission of bioavailability or establishing
bioequivalence of these drug products. * evidence obtained in vivo measuring the bioequivalence, as appropriate, for the
** bioavailability or demonstrating the product being tested.
(1) * * * bioequivalence of the drug product if (b) * * *
(ii) Contains the same active and the drug product meets one of the (4) Well-controlled clinical trials that
inactive ingredients in the same following criteria: establish the safety and effectiveness of
concentration as a drug product that is * * * * * the drug product, for purposes of
the subject of an approved full new drug measuring bioavailability, or
(2) * * *
application or abbreviated new drug appropriately designed comparative
(i) The bioavailability of this other
application. clinical trials, for purposes of
drug product has been measured;
(2) * * * demonstrating bioequivalence. This
(ii) Contains an active ingredient in * * * * * approach is the least accurate, sensitive,
the same dosage form as a drug product (iv) Paragraph (d) of this section does and reproducible of the general
that is the subject of an approved full not apply to delayed release or extended approaches for measuring
new drug application or abbreviated release products. bioavailability or demonstrating
new drug application. * * * * * bioequivalence. * * * This approach
(3) * * * (4) * * * may also be considered sufficiently

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77674 Federal Register / Vol. 67, No. 244 / Thursday, December 19, 2002 / Rules and Regulations

accurate for measuring bioavailability or marketing can be used to measure the § 320.28 [Amended]
demonstrating bioequivalence of dosage following pharmacokinetic data: 13. Section 320.28 Correlation of
forms intended to deliver the active * * * * * bioavailability with an acute
moiety locally, e.g., topical preparations (e) New formulations of active drug pharmacological effect or clinical
for the skin, eye, and mucous ingredients or therapeutic moieties evidence is amended by removing the
membranes; oral dosage forms not approved for marketing. (1) An in vivo word ‘‘controlled’’ and adding in its
intended to be absorbed, e.g., an antacid bioavailability study involving a drug place the word ‘‘extended’’.
or radiopaque medium; and product that is a new dosage form, or a
bronchodilators administered by 14. Section 320.29 is amended by
new salt or ester of an active drug revising the section heading and
inhalation if the onset and duration of ingredient or therapeutic moiety that
pharmacological activity are defined. paragraph (a) and by adding the word
has been approved for marketing can be ‘‘active’’ before the word ‘‘metabolite(s)’’
(5) A currently available in vitro test used to:
acceptable to FDA (usually a dissolution in paragraph (b) to read as follows:
(i) Measure the bioavailability of the
rate test) that ensures human in vivo § 320.29 Analytical methods for an in vivo
new formulation, new dosage form, or
bioavailability. bioavailability or bioequivalence study.
new salt or ester relative to an
(6) Any other approach deemed
appropriate reference material; and (a) The analytical method used in an
adequate by FDA to measure
bioavailability or establish * * * * * in vivo bioavailability or bioequivalence
bioequivalence. 11. Section 320.26 is amended by study to measure the concentration of
(c) FDA may, notwithstanding prior revising the section heading and the active drug ingredient or therapeutic
requirements for measuring paragraph (a)(1) to read as follows: moiety, or its active metabolite(s), in
bioavailability or establishing body fluids or excretory products, or the
§ 320.26 Guidelines on the design of a method used to measure an acute
bioequivalence, require in vivo testing single-dose in vivo bioavailability or
in humans of a product at any time if pharmacological effect shall be
bioequivalence study. demonstrated to be accurate and of
the agency has evidence that the
(a) Basic principles. (1) An in vivo sufficient sensitivity to measure, with
product:
bioavailability or bioequivalence study appropriate precision, the actual
* * * * * should be a single-dose comparison of concentration of the active drug
10. Section 320.25 is amended by: the drug product to be tested and the ingredient or therapeutic moiety, or its
a. Removing paragraph (a)(2); appropriate reference material active metabolite(s), achieved in the
b. Redesignating paragraph (a)(3) as conducted in normal adults. body.
paragraph (a)(2);
* * * * * * * * * *
c. Revising newly redesignated
paragraph (a)(2), paragraph (d)(1), 12. Section 320.27 is amended by: 15. Section 320.30 is amended by
paragraph (e)(1) introductory text, and a. Revising paragraphs (a)(3)(iv), revising paragraph (c) to read as follows:
paragraph (e)(1)(i); (d)(1), and (d)(2);
§ 320.30 Inquiries regarding bioavailability
d. Revising the heading of paragraph b. Removing from paragraph (b)(2) the and bioequivalence requirements and
(f) to read ‘‘Extended release word ‘‘controlled’’ and adding in its review of protocols by the Food and Drug
formulations.’’; place the word ‘‘extended’’; and Administration.
e. Removing from paragraph (f) the c. Adding in paragraph (b)(3)(i) the * * * * *
word ‘‘controlled’’ each time it appears word ‘‘active’’ before the word
and adding in its place the word (c)(1) General inquiries relating to in
‘‘metabolite(s),’’.
‘‘extended’’; and vivo bioavailability requirements and
The additions and revisions read as methodology shall be submitted to the
f. Removing from paragraph (f)(iii) the follows:
word ‘‘noncontrolled’’ and adding in its Food and Drug Administration, Center
place the word ‘‘nonextended’’. § 320.27 Guidelines on the design of a for Drug Evaluation and Research,
The revisions read as follows: multiple-dose in vivo bioavailability study. Office of Clinical Pharmacology and
(a) * * * Biopharmaceutics (HFD–850), 5600
§ 320.25 Guidelines for the conduct of an Fishers Lane, Rockville, MD 20857.
in vivo bioavailability study. (3) * * *
(iv) The drug product is an extended (2) General inquiries relating to
(a) * * * bioequivalence requirements and
release dosage form.
(2) An in vivo bioavailability study is methodology shall be submitted to the
generally done in a normal adult * * * * * Food and Drug Administration, Center
population under standardized (d) Collection of blood or urine for Drug Evaluation and Research,
conditions. In some situations, an in samples. (1) Whenever comparison of Division of Bioequivalence (HFD–650),
vivo bioavailability study in humans the test product and the reference 7500 Standish Pl., Rockville, MD
may preferably and more properly be material is to be based on blood 20855–2773.
done in suitable patients. Critically ill concentration-time curves at steady
patients shall not be included in an in state, appropriate dosage administration § 320.31 [Amended]
vivo bioavailability study unless the and sampling should be carried out to 16. Section 320.31 Applicability of
attending physician determines that document attainment of steady state. requirements regarding an
there is a potential benefit to the patient. (2) Whenever comparison of the test ‘‘Investigational New Drug Application’’
* * * * * product and the reference material is to is amended in paragraph (b)
(d) Previously unmarketed active drug be based on cumulative urinary introductory text by adding after the
ingredients or therapeutic moieties. (1) excretion-time curves at steady state, word ‘‘bioavailability’’ the phrase ‘‘or
An in vivo bioavailability study appropriate dosage administration and bioequivalence’’ and in paragraph (b)(3)
involving a drug product containing an sampling should be carried out to by removing the word ‘‘controlled’’ and
active drug ingredient or therapeutic document attainment of steady state. adding in its place the word
moiety that has not been approved for * * * * * ‘‘extended’’.

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Federal Register / Vol. 67, No. 244 / Thursday, December 19, 2002 / Rules and Regulations 77675

Dated: December 8, 2002. and Radiological Health (HFZ–410), the General and Plastic Surgery Devices
Margaret M. Dotzel, Food and Drug Administration, 9200 Panel (the Panel members) regarding
Assistant Commissioner for Policy. Corporate Blvd., Rockville, MD 20850, reclassification of the absorbable PDS
[FR Doc. 02–31996 Filed 12–18–02; 8:45 am] 301–594–3090. suture. The Panel members
BILLING CODE 4160–01–S SUPPLEMENTARY INFORMATION: recommended that FDA reclassify the
absorbable PDS suture for soft tissue
I. Background approximation, including use in
DEPARTMENT OF HEALTH AND The Federal Food, Drug, and Cosmetic pediatric cardiovascular tissue where
HUMAN SERVICES Act (the act) (21 U.S.C. 301 et seq.), as growth is expected to occur, and
amended by the Medical Device ophthalmic surgery, from class III to
Food and Drug Administration Amendments of 1976 (the 1976 class II. The Panel members also
amendments) (Public Law 94–295), the recommended consensus standards and
21 CFR Part 878 Safe Medical Devices Act of 1990 (the device-specific labeling as the special
[Docket No. 99P–5589]
SMDA) (Public Law 101–629), and the controls that could reasonably assure
Food and Drug Administration the safety and effectiveness of the
Medical Devices; Reclassification and Modernization Act of 1997 (FDAMA) device.
Codification of the Absorbable (Public Law 105–115), established a
III. FDA’s Conclusion
Polydioxanone Surgical Suture comprehensive system for the regulation
of medical devices intended for human FDA considered the Panel members’
AGENCY: Food and Drug Administration, use. Section 513 of the act (21 U.S.C. recommendations that the generic type
HHS. 360c) establishes three categories of device, the absorbable PDS suture for
ACTION: Final rule. (classes) of devices, depending on the soft tissue approximation, be
regulatory controls needed to provide reclassified from class III to class II.
SUMMARY: The Food and Drug After reviewing the data in the petition
reasonable assurance of their safety and
Administration (FDA) is announcing and after considering the Panel
effectiveness. The three categories of
that it has issued an order in the form members’ recommendations and the
devices are class I (general controls),
of a letter to Ethicon, Inc., reclassifying comments, FDA, based on the
class II (special controls), and class III
the absorbable polydioxanone surgical information set forth, issued an order to
(premarket approval).
(PDS) suture intended for use in soft The 1976 amendments broadened the the petitioner on September 4, 2001,
tissue approximation, including use in definition of ‘‘device’’ in section 201(h) reclassifying the absorbable PDS suture,
pediatric cardiovascular tissue where of the act (21 U.S.C. 321(h)) to include and substantially equivalent devices of
growth is expected to occur and certain articles that were once regulated this generic type, from class III to class
ophthalmic surgery, from class III as drugs. Under the 1976 amendments, II. Accordingly, as required under
(premarket approval) to class II (special Congress classified into class III all § 860.136(b)(6), FDA is announcing the
controls). Elsewhere in this issue of the transitional devices, i.e., those devices reclassification of the generic absorbable
Federal Register, FDA is announcing previously regulated as new drugs, PDS suture from class III (premarket
the availability of the guidance including the absorbable PDS suture. approval) into class II (special controls).
document entitled ‘‘Class II Special Section 520(l)(2) of the act (21 U.S.C. The special control capable of providing
Controls Guidance Document: Surgical 360j(l)(2)) provides that the reasonable assurance of safety and
Sutures; Guidance for Industry and manufacturer or importer of a device effectiveness for this device is a
FDA,’’ which is immediately in effect as classified in class III under the guidance document entitled ‘‘Class II
the special control for the PDS suture, transitional provisions may file a Special Controls Guidance Document:
but remains subject to public comment petition for reclassification of the device Surgical Sutures; Guidance for Industry
and possible future revision under the into class I or class II. Procedures for and FDA,’’ which FDA is making
agency’s good guidance practices. The filing and review of classification available elsewhere in this issue of the
agency is reclassifying this device into petitions are set forth in § 860.136 (21 Federal Register. The guidance
class II because new information CFR 860.136). document describes a means by which
supplied by the petitioner indicates that surgical suture devices may comply
special controls, in addition to general II. Regulatory History of the Device with the requirement of special controls
controls, will provide reasonable Under section 520(l)(2) of the act and for class II devices. Any firm submitting
assurance of the safety and effectiveness § 860.136, on August 25, 1999, FDA a premarket notification (510(k)) for a
of the device, and there is sufficient filed a petition submitted by Ethicon, new PDS suture will need to address the
information to establish special Inc., requesting reclassification of the issues covered in the special control
controls. Accordingly, the order is being absorbable PDS suture from class III to guidance. However, the firm needs only
codified in the Code of Federal class II. Class II devices are those to show that its device meets the
Regulations. Any firm submitting a devices for which the general controls recommendations of the guidance or in
premarket notification (510(k)) for a new by themselves are insufficient to some other way provides equivalent
PDS suture will need to address the provide reasonable assurance of safety assurances of safety and effectiveness.
issues covered in the special control and effectiveness, but for which there is The special control guidance document
guidance. However, the firm need only sufficient information to establish reframes the risks identified in the PDS
show that its device meets the special controls to provide such reclassification order to better show
recommendations of the guidance or in assurance, including performance how the mitigating measures
some other way provides equivalent standards, postmarket surveillance, recommended by the guidance are
assurances of safety and effectiveness. patient registries, development and associated with each risk. The clinical
DATES: This rule is effective January 21, dissemination of guidelines, sequelae of the risks identified in the
2003. The reclassification was effective recommendations, and any other order and of the risks identified in the
September 4, 2001. appropriate actions the agency deems guidance are identical. FDA notes that
FOR FURTHER INFORMATION CONTACT: necessary (section 513(a)(1)(B) of the the class II special control guidance
Anthony D. Watson, Center for Devices act). FDA consulted with members of document incorporates consensus

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