Bioavailability and Bioequivalence Requirements; Abbreviated Applications; Proposed Revisions

SUMMARY: The Food and Drug Administration (FDA) is proposing to revise

its regulations on bioavailability and bioequivalence and on the

content and format of an abbreviated application to reflect current FDA

policy and to correct certain typographical and inadvertent errors.

This action is intended to improve the accuracy and clarity of the

regulations.

DATES: Written comments by February 2, 1999. FDA proposes that any

final rule based on this proposal become effective 60 days after its

date of publication in the Federal Register.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,

Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Christine F. Rogers, Center for Drug

Evaluation and Research (HFD-7), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

FDA regulations require persons submitting a new drug application

(NDA) to provide bioavailability information (21 CFR 314.50(c)(2)(vi)

and (d)(3)), and persons submitting an abbreviated new drug application

(ANDA) or abbreviated antibiotic application (AADA) to provide

information pertaining to bioavailability and bioequivalence

(Sec. 314.94(a)(7) and (d)(3) (21 CFR 314.94(a)(7) and (d)(3))).

FDA regulations in part 320 (21 CFR part 320) establish definitions

and requirements for bioavailability and bioequivalence studies. FDA

finalized the bioavailability and bioequivalence regulations on January

7, 1977 (42 FR 1624), and amended these regulations on April 28, 1992

(57 FR 17950). The 1992 amendments were designed to reflect statutory

changes resulting from the Drug Price Competition and Patent Term

Restoration Act of 1984 (Pub. L. 98-417).

Bioavailability, in general, refers to the rate and extent to which

the active ingredient or active moiety is absorbed from a drug product

and becomes available at the site of action. For drug products that are

not intended to be absorbed into the bloodstream, bioavailability may

be assessed by measurements intended to reflect the rate and extent to

which the active ingredient or active moiety becomes available at the

site of action (Sec. 320.1(a)). Bioequivalence, in general, refers to

the absence of a significant difference in the rate and extent to which

the active ingredient or active moiety in pharmaceutical equivalents or

pharmaceutical alternatives becomes available at the site of drug

action when administered at the same molar dose under similar

conditions in an appropriately designed study. Where there is an

intentional difference in rate (e.g., in certain controlled release

dosage forms), certain pharmaceutical equivalents or alternatives may

be considered bioequivalent if there is no significant difference in

the extent to which the active ingredient or moiety from each product

becomes available at the site of drug action (Sec. 320.1(e)).

II. Description of the Proposed Rule

The proposed rule would revise FDA regulations pertaining to

abbreviated applications, bioavailability, and bioequivalence to

reflect current agency policy, to correct typographical and inadvertent

errors, and to clarify existing provisions. The proposed amendments

follow.

Section 314.94(a)(9) establishes information requirements for the

chemistry, manufacturing, and controls section of an abbreviated

application. Section 314.94(a)(9) provides that an abbreviated

application may have different inactive ingredients than the reference

listed drug as long as the applicant identifies and characterizes the

inactive ingredients in the proposed drug product and provides

information demonstrating that the inactive ingredients do not affect

the safety of the drug product. The proposed rule would amend this

section to recognize the possibility that the use of different inactive

ingredients may also affect a product's efficacy.

Section 314.94(a)(9)(v) establishes the requirements for inactive

ingredient changes permitted in drug products intended for topical use.

The proposed rule would revise this section to include solutions for

aerosolization or nebulization as well as nasal solutions. This change

is intended to clarify that these solutions may be characterized as

drug products intended for topical use.

[[Page 64223]]

Section 314.127 (21 CFR 314.127) sets forth the reasons why FDA

would refuse to approve an ANDA. The proposed rule would revise

Sec. 314.127(a)(8) to clarify that, consistent with current FDA policy,

the applicant must show that different inactive ingredients would not

affect a product's efficacy, in addition to the currently required

showing for safety. This revision is necessary because a change in

inactive ingredients may affect safety or efficacy or both. As the

agency stated in the preamble to the proposed rule implementing the

Drug Price Competition and Patent Term Restoration Act of 1984, ``[i]t

is well established that changing the inactive ingredients in a drug

can adversely affect the drug's safety or effectiveness.'' (See 54 FR

28872 at 28902, July 10, 1989.) For example, an inactive ingredient

that increases or decreases an active ingredient's efficacy may affect

the safety of the drug product as well. If a drug is not achieving its

therapeutic purpose, the drug may be unsafe for use. An ineffective

drug may cause a patient to unwittingly delay effective treatment.

Thus, safety and effectiveness are, to a great extent, intertwining

principles.

Section 320.1(c) defines ``pharmaceutical equivalents'' as:

* * * drug products that contain identical amounts of the

identical active drug ingredient, i.e., the same salt or ester of

the same therapeutic moiety, in identical dosage forms, but not

necessarily containing the same inactive ingredients, and that meet

the identical compendial or other applicable standard of identity,

strength, quality, and purity, including potency and, where

applicable, content uniformity, disintegration times and/or

dissolution rates.

This definition has been the source of some confusion with regard

to certain modified release systems, prefilled syringes, and other drug

products that contain a reservoir that facilitates delivery or where

residual volume may vary. In such products, the agency does not

consider the amount that facilitates the action of the delivery system,

but by design is not intended to be delivered to the site of drug

action or to have any direct therapeutic effect, to be ``active

ingredient'' for the purposes of evaluating the pharmaceutical

equivalence of a drug product.

Therefore, to clarify the definition of ``pharmaceutical

equivalents'' with regard to certain drug products such as prefilled

syringes and those that use modified release systems, the agency is

proposing to revise the definition of ``pharmaceutical equivalents'' in

Sec. 320.1(c) to state:

* * * drug products in identical dosage forms that contain

identical amounts of the identical active drug ingredient, i.e., the

same salt or ester of the same therapeutic moiety or, in the case of

modified release dosage forms that require a reservoir or overage or

such forms as prefilled syringes where residual volume may vary,

that deliver identical amounts of the active drug ingredient over

the identical dosing period; do not necessarily contain the same

inactive ingredients; and meet the identical compendial or other

applicable standard of identity, strength, quality, and purity,

including potency and, where applicable, content uniformity,

disintegration times, and/or dissolution rates.

Subpart B of part 320 describes procedures for determining the

bioavailability or bioequivalence of drug products, and refers to

evidence that ``demonstrates'' in vivo bioavailability and

bioequivalence. The proposed rule would modify current Secs. 320.21,

320.22, 320.23, 320.24, and 320.25 to clarify that although

bioequivalence may be ``demonstrated'' or ``established,''

bioavailability can only be ``measured.'' These verb changes also

require that the words ``in vivo'' precede the word ``bioequivalence.''

Section 320.21 sets forth the requirements for submission of in

vivo bioavailability and bioequivalence data. Section 320.21(b)(1)

provides that any person submitting an abbreviated application must

submit evidence demonstrating that the proposed drug product is

bioequivalent to the reference listed drug or, under Sec. 320.21(b)(2),

provide ``[i]nformation to show that the drug product is bioequivalent

to the reference listed drug which would permit FDA to waive the

submission of evidence demonstrating bioequivalence * * *.'' The

proposed rule would revise Sec. 320.21(b)(2) to clarify that the waiver

would only pertain to the submission of evidence demonstrating the in

vivo determination of bioequivalence.

Section 320.21(c)(1) provides that any person submitting a

supplemental application to FDA must provide evidence or information

regarding the product's bioavailability or bioequivalence if the

supplemental application proposes ``[a] change in the manufacturing

process, including a change in product formulation or dosage strength,

beyond the variations provided for in the approved application.'' The

proposed rule would amend this provision to include a change in the

manufacturing site because such a change may affect the bioavailability

or bioequivalence of the drug product because of equipment, personnel,

or environmental changes.

Section 320.21(d) states that ``FDA may approve a full new drug

application * * * that does not contain evidence of in vivo

bioavailability or information to permit waiver of the requirement for

in vivo bioavailability data,'' if, among other things, ``[t]he

application was under review by FDA on July 7, 1977''

(Sec. 320.21(d)(1).) The agency is proposing to remove this paragraph

because it has become outdated.

Section 320.21(f) inaccurately includes a reference to criteria set

forth in Sec. 320.24 as containing information under which FDA could

waive the requirement for submission of evidence demonstrating in vivo

bioavailability or bioequivalence. The proposed rule would replace the

reference to Sec. 320.24 with Sec. 320.22.

Proposed Sec. 320.22(a) would address another typographical error.

Current Sec. 320.22(a) states that ``[e]xcept as provided in paragraph

(g) of this section,'' FDA shall waive the requirement for the

submission of evidence of in vivo bioavailability or bioequivalence

under certain conditions. The proposed rule would substitute paragraph

(f) for the reference to paragraph (g).

Section 320.22(b) sets forth the criteria under which a drug

product's in vivo bioavailability or bioequivalence may be considered

self-evident based on other data in an application showing that the

proposed drug product is identical in certain respects to the ``drug

product that is the subject of an approved full new drug application''

(see Sec. 320.22(b)(1)(ii), (b)(2)(ii), and (b)(3)(ii)). The proposed

rule would replace ``approved full new drug application'' with

``approved full new drug application or abbreviated new drug

application.'' This revision recognizes those instances when an

approved abbreviated new drug application might be the reference listed

drug because there is no approved full new drug application. The

proposed rule would make a similar change to Sec. 320.22(b)(3)(iii)

because this provision also refers to a ``drug product that is the

subject of the approved full new drug application * * *.''

Section 320.22(b)(3)(i) sets forth the criteria for waiver of the

in vivo bioavailability or bioequivalence of a drug product that is ``a

solution for application to the skin, an oral solution, elixir, syrup,

tincture, or similar other solubilized form'' intended for either local

or systemic effect. The proposed rule would amend Sec. 320.22(b)(3)(i)

to include a ``solution for aerosolization or nebulization'' and a

``nasal solution'' to clarify that ``similar other solubilized form''

includes solutions for aerosolization or nebulization and nasal

solutions.

Section 320.22(c) provides that ``FDA shall waive the requirement

for the submission of evidence demonstrating

[[Page 64224]]

the in vivo bioavailability of a solid oral dosage form (other than an

enteric coated or controlled release dosage form) * * *'' unless, among

other things, ``FDA has evaluated the drug product under the criteria

set forth in Sec. 320.32 * * *.'' The reference to Sec. 320.32 is a

typographical error. The proposed rule would refer to Sec. 320.33

because the relevant criteria are found in that provision. In addition,

the proposed rule would clarify that FDA may waive this requirement not

only for the submission of evidence of in vivo bioavailability but also

for the submission of evidence of in vivo bioequivalence.

The proposed rule would also amend Sec. 320.22(c) because ``delayed

release'' is the preferred terminology for ``enteric coated'' and

``extended release'' is the preferred terminology for ``controlled

release.''

Under Sec. 320.22(e), ``FDA, for good cause, may waive a

requirement for the submission of evidence of in vivo bioavailability

if waiver is compatible with the protection of the public health * *

*.'' When the agency revised and finalized the regulations in 1992, it

intended that Sec. 320.22(e) clearly include waiver of in vivo

bioequivalence testing, as the heading of the section suggests. Indeed,

waiver of the submission of in vivo bioavailability data is related to

waiver of in vivo bioequivalence testing in that bioequivalence is an

assessment of comparative bioavailability. Because there may be some

confusion about the scope of Sec. 320.22(e), the proposed rule would

clarify that FDA may, for good cause, waive not only the submission of

evidence of in vivo bioavailability but also the submission of evidence

of in vivo bioequivalence, if such a waiver is compatible with the

protection of the public health. Such a waiver may be appropriate in

cases where an abbreviated application uses inactive ingredients

different from those in the reference listed drug (see

Sec. 314.94(a)(9)), and thus the other provisions regarding a waiver of

a the requirement for the submission of evidence of in vivo

bioavailability or bioequivalence do not apply. In such cases, a waiver

of the submission of evidence of in vivo bioavailability or

bioequivalence may, for good cause, be granted if compatible with the

protection of the public health.

Section 320.24 sets forth the various types of evidence needed to

establish bioavailability or bioequivalence. The agency is removing

Sec. 320.24(b)(1)(iii) because FDA does not encourage the use of

animals in vivo bioavailability studies. Section 320.24(b)(5), which

focuses on one method, in vitro testing, contains a typographical

error, stating that the in vitro test acceptable to FDA is ``unusually

a dissolution rate test.'' The proposed rule would replace

``unusually'' with ``usually.''

Section 320.25 provides guidelines for the conduct of an in vivo

bioavailability study. Section 320.25(a)(2) provides that ``[a]n in

vivo bioavailability study shall not be conducted in humans if an

appropriate animal model exists and correlation of results in animals

and humans has been demonstrated * * *.'' The agency is proposing to

remove Sec. 320.25(a)(2) because FDA does not encourage the use of

animals in vivo bioavailability studies.

Section 320.25(d)(1) describes the purpose of a bioavailability

study involving a drug product containing an active drug ingredient or

therapeutic moiety that has not been approved for marketing. The agency

has determined that Sec. 320.25(d)(1) is inaccurate because it actually

describes the purpose of a pharmacokinetic study, rather than a

bioavailability study. Thus, the proposed rule would revise the

introductory text of Sec. 320.25(d)(1) to read ``An in vivo

bioavailability study involving a drug product containing an active

drug ingredient or therapeutic moiety that has not been approved for

marketing can be used to measure the following pharmacokinetic data: *

* *.''

Section 320.25(e)(1) describes the purpose of an in vivo

bioavailability study involving a drug product that is a new

formulation, a new dosage form, or a new salt or ester of an active

drug ingredient or therapeutic moiety that has been approved for

marketing. The agency has determined that Sec. 320.25(e)(1) is

inaccurate because it also describes the purpose of a pharmacokinetic

study, not a bioavailability study. Thus, the proposed rule would

revise the introductory text of Sec. 320.25(e)(1) to read ``An in vivo

bioavailability study involving a drug product that is a new

formulation, a new dosage form, or a new salt or ester of an active

drug ingredient or therapeutic moiety that has been approved for

marketing can be used to: * * *.''

Section 320.26 provides guidance on the design of a single-dose in

vivo bioavailability study, and Sec. 320.27 provides guidance on the

design of a multiple-dose in vivo bioavailability study. The proposed

rule would add the word ``bioequivalence'' after ``bioavailability''

throughout these two sections because Secs. 320.26 and 320.27 are also

applicable to in vivo bioequivalence studies. This revision reflects

current FDA policy. The proposed rule would also amend Secs. 320.28 and

320.29 to include reference to bioequivalence because these sections

are also applicable to in vivo bioequivalence studies.

The proposed rule would also amend Sec. 320.26(b)(2)(i) by

replacing ``three'' with ``five.'' The proposed rule would also insert

the word ``active'' before ``metabolite(s)'' in Secs. 320.26(b)(2)(i)

and 320.27(b)(3)(i). FDA is proposing these revisions because the drug

elimination period (wash-out period) of three times the half-life of

the active drug ingredient or therapeutic moiety, or its active

metabolite(s), is inadequate, and because current analytical methods

exist that usually are capable of detecting drug concentrations after

five times the half-life of the active drug ingredient or therapeutic

moiety, or its active metabolite(s).

Section 320.27(d)(1) states that, for the collection of blood

samples during multiple-dose in vivo bioavailability studies, the

maximum (Cmax) and minimum (Cmin) values should be defined on 2 or more

consecutive days to establish that steady-state conditions are

achieved. FDA no longer uses Cmax values in the determination of

steady-state conditions and, in some cases, the predose trough level

may not be the observed Cmin value. In addition, FDA recommends that

sampling be done for at least 3 consecutive days. Therefore, the

proposed rule would revise Sec. 320.27(d)(1) to state:

Whenever comparison of the test product and the reference

material is to be based on blood concentration-time curves at

steady-state, sufficient samples of blood should be taken to define

adequately the predose blood concentration on 3 or more consecutive

days to establish that steady-state conditions are achieved.

Section 320.27(d)(2) states that ``[w]henever comparison of the

test product and the reference material is to be based on cumulative

urinary excretion-time curves at steady-state, sufficient samples of

urine should be taken to define the rate and extent of urinary

excretion on 2 or more consecutive days to establish that steady-state

conditions are achieved.'' For the reasons stated previously, the

proposed rule would revise this paragraph to state:

Whenever comparison of the test product and the reference

material is to be based on cumulative urinary excretion-time curves

at steady-state, sufficient samples of urine should be taken to

define the rate and extent of urinary excretion on 3 or more

consecutive days to establish that steady-state conditions are

achieved.

Section 320.30(c)(1) directs inquiries on bioavailability to the

Division of Biopharmaceutics in the Center for Drug Evaluation and

Research. The proposal

[[Page 64225]]

would update the name of the Division of Biopharmaceutics because it is

now called the ``Office of Clinical Pharmacology and Biopharmaceutics''

(HFD-850).

Section 320.30(c)(2) directs inquiries on bioequivalence

requirements and methodology to the Division of Bioequivalence in the

Center for Drug Evaluation and Research. The proposal would update the

mailing address for the Division of Bioequivalence because it is now

located at Metro Park North II, 7500 Standish Pl., Rockville, MD 20855-

2773.

Section 320.31 discusses the applicability of the investigational

new drug application requirements to certain bioavailability or

bioequivalence studies. Although FDA intended that this section apply

to bioavailability or bioequivalence studies, Sec. 320.31(b) only

refers to bioavailability studies. The proposal would insert the words

``or bioequivalence'' after the word ``bioavailability'' in the

introductory text of Sec. 320.31(b) to clarify that this section

applies to bioequivalence studies as well.

Broader issues concerning FDA's interpretation and application of

the regulations applicable to bioequivalence issues have recently been

the subject of controversy. The ability to characterize and quantify

the components of drug products has evolved and continues to evolve

with advances in the science of analytical chemistry. A more refined

characterization of a drug product may complicate determinations about

the components or quantity of components that may affect the safety of

the drug product or contribute to its pharmacological effect. Changes

to definitional concepts such as active and inactive ingredients are

beyond the scope of these, for the most part, technical revisions to

the regulations. However, FDA intends to address such issues in a

future proposal.

III. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive

Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages). Under the Regulatory Flexibility Act, unless an agency

certifies that a rule will not have a significant impact on small

entities, the agency must analyze regulatory options that would

minimize the impact of the rule on small entities. Title II of the

Unfunded Mandates Reform Act (Pub. L. 104-114) (in section 202)

requires that agencies prepare an assessment of anticipated costs and

benefits before proposing any rule that may result in an expenditure in

any 1 year by State, local, and tribal governments, in the aggregate,

or by the private sector, of $100 million or more (adjusted annually

for inflation).

The agency has reviewed this proposed rule and has determined that

it is consistent with the regulatory philosophy and principles

identified in Executive Order 12866, and these two statutes. With

respect to the Regulatory Flexibility Act, the agency certifies that

the rule will not have a significant economic impact on a substantial

number of small entities. Because the proposed rule does not impose any

mandates on State, local, or tribal governments, or the private sector

that will result in a 1-year expenditure of $100 million or more, FDA

is not required to perform a cost-benefit analysis under the Unfunded

Mandates Reform Act.

The proposed rule would amend the bioavailability and

bioequivalence regulations to reflect current FDA policy.

IV. Paperwork Reduction Act of 1995

FDA tentatively concludes that this proposed rule contains no

collections of information. Therefore, clearance by the Office of

Management and Budget under the Paperwork Reduction Act of 1995 is not

required.

V. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is

of a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

VI. Request for Comments

Interested persons may, on or before February 2, 1999, submit to

the Dockets Management Branch (address above) written comments

regarding this proposal. Two copies of any comments are to be

submitted, except that individuals may submit one copy. Comments are to

be identified with the docket number found in brackets in the heading

of this document. Received comments may be seen in the office above

between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects

21 CFR Part 314

Administrative practice and procedure, Confidential business

information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 320

Drugs, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act and the

authority delegated to the Commissioner of Food and Drugs, it is

proposed that 21 CFR parts 314 and 320 be amended as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN

ANTIBIOTIC DRUG

1. The authority citation for 21 CFR part 314 continues to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 371,

374, 379e.

2. Section 314.94 is amended in paragraph (a)(9)(ii) and the second

sentence of paragraphs (a)(9)(iii) and (a)(9)(iv) by adding after the

word ``safety'' the phrase ``or efficacy'' each time it appears, and by

revising paragraph (a)(9)(v) to read as follows:

Sec. 314.94 Content and format of an abbreviated application.

* * * * *

(a) * * *

(9) * * *

(v) Inactive ingredient changes permitted in drug products intended

for topical use. Generally, a drug product intended for topical use,

solutions for aerosolization or nebulization, and nasal solutions shall

contain the same inactive ingredients as the reference listed drug

identified by the applicant under paragraph (a)(3) of this section.

However, an abbreviated application may include different inactive

ingredients provided that the applicant identifies and characterizes

the differences and provides information demonstrating that the

differences do not affect the safety or efficacy of the proposed drug

product.

* * * * *

Sec. 314.127 [Amended]

3. Section 314.127 Refusal to approve an abbreviated new drug

application is amended in the introductory text of paragraph

(a)(8)(ii)(A), and in paragraphs (a)(8)(ii)(B) and (a)(8)(ii)(C) by

adding after the word ``safety'' the phrase ``or efficacy'' each time

it appears.

[[Page 64226]]

PART 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS

4. The authority citation for 21 CFR part 320 continues to read as

follows:

Authority: 21 U.S.C. 321, 351, 352, 355, 357, 371.

5. Section 320.1 is amended by revising paragraph (c) to read as

follows:

Sec. 320.1 Definitions.

* * * * *

(c) Pharmaceutical equivalents means drug products in identical

dosage forms that contain identical amounts of the identical active

drug ingredient, i.e., the same salt or ester of the same therapeutic

moiety, or, in the case of modified release dosage forms that require a

reservoir or overage or such forms as prefilled syringes where residual

volume may vary, that deliver identical amounts of the active drug

ingredient over the identical dosing period; do not necessarily contain

the same inactive ingredients; and meet the identical compendial or

other applicable standard of identity, strength, quality, and purity,

including potency and, where applicable, content uniformity,

disintegration times, and/or dissolution rates.

* * * * *

6. Section 320.21 is amended by removing paragraph (d)(1) and

redesignating paragraphs (d)(2) and (d)(3) as paragraphs (d)(1) and

(d)(2), respectively, and by revising newly redesignated (d)(2)(i) and

(d)(2)(ii); and by revising paragraphs (a)(1), (a)(2), (b)(1), (b)(2),

(c)(1), (e), and (f), the introductory text of paragraph (g), and

paragraphs (g)(2) and (h) to read as follows:

Sec. 320.21 Requirements for submission of in vivo bioavailability

and bioequivalence data.

(a) * * *

(1) Evidence measuring the in vivo bioavailability of the drug

product that is the subject of the application; or

(2) Information to permit FDA to waive the submission of evidence

measuring in vivo bioavailability.

(b) * * *

(1) Evidence demonstrating that the drug product that is the

subject of the abbreviated new drug application is bioequivalent to the

reference listed drug (defined in Sec. 314.3(b) of this chapter); or

(2) Information to show that the drug product is bioequivalent to

the reference listed drug which would permit FDA to waive the

submission of evidence demonstrating in vivo bioequivalence as provided

in paragraph (f) of this section.

(c) * * *

(1) A change in manufacturing site as well as a change in the

manufacturing process, including a change in product formulation or

dosage strength, beyond the variations provided for in the approved

application.

* * * * *

(d) * * *

(2) * * *

(i) Evidence measuring the in vivo bioavailability and

demonstrating the in vivo bioequivalence of the drug product that is

the subject of the application; or

(ii) Information to permit FDA to waive measurement of in vivo

bioavailability.

(e) Evidence measuring the in vivo bioavailability and

demonstrating the in vivo bioequivalence of a drug product shall be

obtained using one of the approaches for determining bioavailability

set forth in Sec. 320.24.

(f) Information to permit FDA to waive the submission of evidence

measuring the in vivo bioavailability or demonstrating the in vivo

bioequivalence shall meet the criteria set forth in Sec. 320.22.

(g) Any person holding an approved full or abbreviated new drug

application shall submit to FDA a supplemental application containing

new evidence measuring the in vivo bioavailability or demonstrating the

in vivo bioequivalence of the drug product that is the subject of the

application if notified by FDA that:

* * * * *

(2) There are data measuring significant intra-batch and batch-to-

batch variability, e.g., plus or minus 25 percent, in the

bioavailability of the drug product.

(h) The requirements of this section regarding the submission of

evidence measuring the in vivo bioavailability or demonstrating the in

vivo bioequivalence apply only to a full or abbreviated new drug

application or a supplemental application for a finished dosage

formulation.

7. Section 320.22 is amended by revising paragraph (a), the second

sentence of paragraph (b), paragraphs (b)(1)(ii), (b)(2)(ii),

(b)(3)(i), (b)(3)(ii), (b)(3)(iii), and (c), the introductory text of

paragraph (d), paragraphs (d)(2)(i) and (d)(4)(i), and the first

sentence of paragraph (e) to read as follows:

Sec. 320.22 Criteria for waiver of evidence of in vivo bioavailability

or bioequivalence.

(a) Any person submitting a full or abbreviated new drug

application, or a supplemental application proposing any of the changes

set forth in Sec. 320.21(c), may request FDA to waive the requirement

for the submission of evidence measuring the in vivo bioavailability or

demonstrating the in vivo bioequivalence of the drug product that is

the subject of the application. An applicant shall submit a request for

waiver with the application. Except as provided in paragraph (f) of

this section, FDA shall waive the requirement for the submission of

evidence of in vivo bioavailability or bioequivalence if the drug

product meets any of the provisions of paragraphs (b), (c), (d), or (e)

of this section.

(b) * * * FDA shall waive the requirement for the submission of

evidence obtained in vivo measuring the bioavailability or

demonstrating the bioequivalence of these drug products. * * *

(1) * * *

(ii) Contains the same active and inactive ingredients in the same

concentration as a drug product that is the subject of an approved full

new drug application or abbreviated new drug application.

(2) * * *

(ii) Contains an active ingredient in the same dosage form as a

drug product that is the subject of an approved full new drug

application or abbreviated new drug application.

(3) * * *

(i) Is a solution for application to the skin, an oral solution,

elixir, syrup, tincture, a solution for aerosolization or nebulization,

a nasal solution, or similar other solubilized form.

(ii) Contains an active drug ingredient in the same concentration

and dosage form as a drug product that is the subject of an approved

full new drug application or abbreviated new drug application; and

(iii) Contains no inactive ingredient or other change in

formulation from the drug product that is the subject of the approved

full new drug application or abbreviated new drug application that may

significantly affect absorption of the active drug ingredient or active

moiety.

(c) FDA shall waive the requirement for the submission of evidence

measuring the in vivo bioavailability or demonstrating the in vivo

bioequivalence of a solid oral dosage form (other than a delayed

release or extended release dosage form) of a drug product determined

to be effective for at least one indication in a Drug Efficacy Study

Implementation notice or which is identical, related, or similar to

such a drug product under Sec. 310.6 of this chapter unless FDA has

evaluated the drug product under the criteria set forth in Sec. 320.33,

included the drug product in the Approved Drug Products with

Therapeutic Equivalence Evaluations List, and rated the drug product as

[[Page 64227]]

having a known or potential bioequivalence problem. A drug product so

rated reflects a determination by FDA that an in vivo bioequivalence

study is required.

(d) For certain drug products, bioavailability may be measured or

bioequivalence may be demonstrated by evidence obtained in vitro in

lieu of in vivo data. FDA shall waive the requirement for the

submission of evidence obtained in vivo measuring the bioavailability

or demonstrating the bioequivalence of the drug product if the drug

product meets one of the following criteria:

* * * * *

(2) * * *

(i) The bioavailability of this other drug product has been

measured;

* * * * *

(4) * * *

(i) The bioavailability of the other product has been measured; and

* * * * *

(e) FDA, for good cause, may waive a requirement for the submission

of evidence of in vivo bioavailability or bioequivalence if waiver is

compatible with the protection of the public health. * * *

* * * * *

8. Section 320.23 is amended by revising the section heading and

the first sentence of paragraph (a)(1) to read as follows:

Sec. 320.23 Basis for measuring in vivo bioavailability or

demonstrating bioequivalence.

(a)(1) The in vivo bioavailability of a drug product is measured if

the product's rate and extent of absorption, as determined by

comparison of measured parameters, e.g., concentration of the active

drug ingredient in the blood, urinary excretion rates, or

pharmacological effects, do not indicate a significant difference from

the reference material's rate and extent of absorption. * * *

* * * * *

9. Section 320.24 is amended by revising the section heading and

the first, second, and last sentences of paragraph (a), by removing

paragraph (b)(1)(iii), by revising the first, second, and last

sentences of paragraph (b)(4), paragraphs (b)(5) and (b)(6), and the

introductory text of paragraph (c) to read as follows:

Sec. 320.24 Types of evidence to measure bioavailability or establish

bioequivalence.

(a) Bioavailability may be measured or bioequivalence may be

demonstrated by several in vivo and in vitro methods. FDA may require

in vivo or in vitro testing, or both, to measure the bioavailability of

a drug product or establish the bioequivalence of specific drug

products. * * * The method used must be capable of measuring

bioavailability or establishing bioequivalence, as appropriate, for the

product being tested.

(b) * * *

(4) Well-controlled clinical trials that establish the safety and

effectiveness of the drug product, for purposes of measuring

bioavailability, or appropriately designed comparative clinical trials,

for purposes of demonstrating bioequivalence. This approach is the

least accurate, sensitive, and reproducible of the general approaches

for measuring bioavailability or demonstrating bioequivalence. * * *

This approach may also be considered sufficiently accurate for

measuring bioavailability or demonstrating bioequivalence of dosage

forms intended to deliver the active moiety locally, e.g., topical

preparations for the skin, eye, and mucous membranes; oral dosage forms

not intended to be absorbed, e.g., an antacid or radiopaque medium; and

bronchodilators administered by inhalation if the onset and duration of

pharmacological activity are defined.

(5) A currently available in vitro test acceptable to FDA (usually

a dissolution rate test) that ensures human in vivo bioavailability.

(6) Any other approach deemed adequate by FDA to measure

bioavailability or establish bioequivalence.

(c) FDA may, notwithstanding prior requirements for measuring

bioavailability or establishing bioequivalence, require in vivo testing

in humans of a product at any time if the agency has evidence that the

product:

* * * * *

10. Section 320.25 is amended by removing paragraph (a)(2), by

redesignating paragraph (a)(3) as paragraph (a)(2), and by revising

paragraph (d)(1), the introductory text of paragraph (e)(1), and

paragraph (e)(1)(i) to read as follows:

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

study.

* * * * *

(d) Previously unmarketed active drug ingredients or therapeutic

moieties. (1) An in vivo bioavailability study involving a drug product

containing an active drug ingredient or therapeutic moiety that has not

been approved for marketing can be used to measure the following

pharmacokinetic data:

* * * * *

(e) New formulations of active drug ingredients or therapeutic

moieties approved for marketing. (1) An in vivo bioavailability study

involving a drug product that is a new dosage form, or a new salt or

ester of an active drug ingredient or therapeutic moiety that has been

approved for marketing can be used to:

(i) Measure the bioavailability of the new formulation, new dosage

form, or new salt or ester relative to an appropriate reference

material; and

* * * * *

11. Section 320.26 is amended by revising the section heading and

paragraphs (a)(1) and (b)(2)(i) to read as follows:

Sec. 320.26 Guidelines on the design of a single-dose in vivo

bioavailability or bioequivalence study.

(a) Basic principles. (1) An in vivo bioavailability or

bioequivalence study should be a single-dose comparison of the drug

product to be tested and the appropriate reference material conducted

in normal adults.

* * * * *

(b) * * *

(2) * * *

(i) At least five times the half-life of the active drug ingredient

or therapeutic moiety, or its active metabolite(s), measured in the

blood or urine; or

* * * * *

12. Section 320.27 is amended by revising the section heading,

introductory text of paragraph (a)(3), paragraphs (d)(1), (d)(2), and

(e)(3); and by adding in paragraph (b)(3)(i) the word ``active'' before

the word ``metabolite(s),'' to read as follows:

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

bioavailability or bioequivalence study.

(a) * * *

(3) A multiple-dose study may be required to determine the

bioavailability or bioequivalence of a drug product in the following

circumstances:

* * * * *

(d) Collection of blood or urine samples. (1) Whenever comparison

of the test product and the reference material is to be based on blood

concentration-time curves at steady-state, sufficient samples of blood

should be taken to define adequately the predose blood concentration on

3 or more consecutive days to establish that steady-state conditions

are achieved.

(2) Whenever comparison of the test product and the reference

material is to be based on cumulative urinary excretion-time curves at

steady-state, sufficient samples of urine should be taken to define the

rate and extent of

[[Page 64228]]

urinary excretion on 3 or more consecutive days to establish that

steady-state conditions are achieved.

* * * * *

(e) * * *

(3) Other methods based on valid scientific reasons should be used

to determine the bioavailability or bioequivalence of a drug product

having dose-dependent kinetics (nonlinear system).

* * * * *

13. Section 320.29 is amended by revising the section heading and

paragraph (a) to read as follows:

Sec. 320.29 Analytical methods for an vivo bioavailability or

bioequivalence study.

(a) The analytical method used in an in vivo bioavailability or

bioequivalence study to measure the concentration of the active drug

ingredient or therapeutic moiety, or its metabolite(s), in body fluids

or excretory products, or the method used to measure an acute

pharmacological effect shall be demonstrated to be accurate and of

sufficient sensitivity to measure, with appropriate precision, the

actual concentration of the active drug ingredient or therapeutic

moiety, or its metabolite(s), achieved in the body.

* * * * *

14. Section 320.30 is amended by revising paragraph (c) to read as

follows:

Sec. 320.30 Inquiries regarding bioavailability and bioequivalence

requirements and review of protocols by the Food and Drug

Administration.

* * * * *

(c)(1) General inquiries relating to in vivo bioavailability

requirements and methodology shall be submitted to the Food and Drug

Administration, Center for Drug Evaluation and Research, Office of

Clinical Pharmacology and Biopharmaceutics (HFD-850), 5600 Fishers

Lane, Rockville, MD 20857.

(2) General inquiries relating to bioequivalence requirements and

methodology shall be submitted to the Food and Drug Administration,

Center for Drug Evaluation and Research, Division of Bioequivalence

(HFD-650), 7500 Standish Pl., Rockville, MD 20855-2773.

Sec. 320.31 [Amended]

15. Section 320.31 Applicability of requirements regarding an

``Investigational New Drug Application is amended in the introductory

text of paragraph (b) by adding after the word ``bioavailability'' the

phrase ``or bioequivalence''.

Dated: November 5, 1998.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 98-30880 Filed 11-18-98; 8:45 am]

BILLING CODE 4160-01-F