Federal Register / Vol. 65, No. 209 / Friday, October 27, 2000 / Notices 64449

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 00D–1513]

Guidance for Industry on

Bioavailability and Bioequivalence

Studies for Orally Administered Drug

Products—General Considerations;

Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is announcing the

availability of a guidance for industry

entitled ‘‘Bioavailability and

Bioequivalence Studies for Orally

Administered Drug Products—General

Considerations.’’ This guidance

provides recommendations to sponsors

and applicants intending to submit

bioavailability (BA) and/or

bioequivalence (BE) information on

investigational new drug applications

(IND’s), new drug applications (NDA’s),

abbreviated new drug applications

(ANDA’s), and their supplements, to the

Center for Drug Evaluation and Research

(CDER). This guidance provides general

information on how to comply with the

BA and BE requirements for orally

administered dosage forms under the

bioavailability and bioequivalence

requirements regulations. It is one of a

set of planned core guidances designed

to reduce or eliminate the need for FDA

drug-specific guidances.

DATES: Submit written comments on

agency guidances at any time.

ADDRESSES: Copies of this guidance for

industry are available on the Internet at

http://www.fda.gov/cder/guidance/

index.htm. Submit written requests for

single copies of ‘‘Bioavailability and

Bioequivalence Studies for Orally

Administered Drug Products—General

Considerations’’ to the Drug Information

Branch (HFD–210), Center for Drug

Evaluation and Research, Food and

Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857. Send one

self-addressed adhesive label to assist

that office in processing your requests.

Submit written comments on the

guidance to the Dockets Management

Branch (HFA–305), Food and Drug

Administration, 5630 Fishers Lane, rm.

1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: MeiLing Chen, Center for Drug Evaluation

and Research (HFD–350), Food and

Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–594–

5688.

SUPPLEMENTARY INFORMATION:

I. Background

FDA is announcing the availability of

a guidance for industry entitled

‘‘Bioavailability and Bioequivalence

Studies for Orally Administered Drug

Products—General Considerations.’’

This guidance provides

recommendations to sponsors and

applicants intending to provide BA and

BE information in IND’s, NDA’s,

ANDA’s, and their supplements that

complies with the BA and BE

requirements in part 320 (21 CFR part

320) as it applies to dosage forms

intended for oral administration.

In September 1999, FDA announced

the availability of a draft guidance

entitled ‘‘BA and BE Studies for Orally

Administered Drug Products—General

Considerations’’ (64 FR 48409,

September 3, 1999). When the draft

guidance was published, FDA requested

comments on the use of the new criteria.

A total of 16 public comments were

received. Most of these comments were

supportive of the recommendations in

the draft guidance, but FDA received a

number of comments that expressed

concern about the use of the individual

BE criterion.

The public comments fell into four

general categories as follows: (1)

Comments on the justification for an

individual BE criterion (absence of

documentation of public health risk,

absence of evidence that subject-byformulation interaction is clinically

relevant); (2) comments on the burden

of conducting replicate study designs

(recruitment costs, institutional review

board approval, capacity constraints,

study delays, increased monitoring for

adverse drug reactions, subject

dropouts, increased drug exposure, and

increased volume of blood collected);

(3) comments on statistical issues

(aggregate versus disaggregate criterion,

discontinuity, and mean/variance tradeoff); and (4) miscellaneous comments

(experimental aspects of 2-year period

recommended in the notice, absence of

community consensus, barriers to

international harmonization and

globalization).

II. Discussion

Many aspects of this guidance

represent departures from past practices

used to document BE. The general

intent of many of these changes is to

reduce the regulatory burden while

maintaining sound scientific principles

consistent with public health objectives.

Examples of ways these changes might

reduce the regulatory burden include:

(1) Enabling biowaivers (i.e., waivers of

in vivo BE studies) for lower strengths

of modified-release dosage forms; (2)

eliminating multiple dose BE studies for

modified-release dosage forms; (3)

enabling biowavers for higher strengths

of immediate-release dosage forms; and

(4) reducing emphasis on measuring

metabolites in BE studies.

FDA acknowledges the public

concerns about the use of the individual

criterion for BE studies. These concerns

were also considered in a meeting of the

Advisory Committee for Pharmaceutical

Science on September 23, 1999

(September 23 meeting). The committee

concluded that replicate study designs

should be recommended for modified

release drug products and should be

strongly encouraged for other drug

products, subject to certain exceptions.

In finalizing the guidance, FDA has

followed the advisory committee’s

recommendations. FDA believes that

replicate study designs offer significant

advantages compared to nonreplicate

designs. Replicate study designs: (1)

Allow comparison of within-subject

variances for the test and reference

products; (2) indicate whether a test

product exhibits higher or lower withinsubject variability in the BA measures

when compared to the reference

product; (3) suggest whether a subjectby-formulation interaction may be

present; (4) provide more information

about factors underlying formulation

performance; and (5) reduce the number

of subjects needed in the BE study.

In accordance with the advisory

committee’s recommendation, FDA

recommends in the guidance the use of

an average BE criterion for both

replicate and nonreplicate studies. A

further committee conclusion in the

September 23 meeting was that an

individual BE criterion can be used to

allow market access of drug products in

compelling circumstances. For this

reason, the guidance states that sponsors

have the option to choose an individual

criterion for highly variable drugs. The

use of an individual criterion with

reference-scaling in this circumstance

can permit a further reduction in the

number of subjects in BE studies.

Reduction in the number of subjects in

BE studies of highly variable drugs is in

keeping with the basic regulatory

principle that no unnecessary human

research should be done (§ 320.25(a)(1)).

By continuing to recommend the use

of the average BE criterion in most

circumstances, the agency has

addressed many of the public comments

expressing concern about the use of the

individual BE criterion. To avoid a large

test and reference difference, constraint

on the allowable difference has been

recommended in this guidance. Use of

the individual BE criterion for highly

64450 Federal Register / Vol. 65, No. 209 / Friday, October 27, 2000 / Notices

variable drugs is expected to occur

rarely. In these instances, FDA believes

that all relevant statistical issues have

been sufficiently resolved and that no

important public health risk will arise if

the criterion is used to allow market

access.

This guidance replaces the following

guidances: (1) ‘‘Guidelines for the

Evaluation of Controlled Release Drug

Products’’ (April 1984); (2) ‘‘Oral

Extended (Controlled) Release Dosage

Form: In Vivo Bioequivalence and In

Vitro Dissolution Testing’’ (September

1993); (3) ‘‘Statistical Procedures for

Bioequivalence Studies Using a

Standard Two-Treatment Crossover

Design’’ (July 1992); (4) the preliminary

draft guidance on ‘‘In Vivo

Bioequivalence Studies Based on

Population and Individual

Bioequivalence Approaches’’ (October

1997), and (5) the draft guidance on ‘‘BA

and BE Studies for Orally Administered

Drug Products—General

Considerations.’’ This guidance

supersedes any prior guidance, or any

relevant part of a prior guidance issued

to assist sponsors in meeting the

requirements in part 320.

This level 1 guidance is being issued

consistent with FDA’s good guidance

practices (65 FR 56468, September 19,

2000). This guidance document

represents the agency’s current thinking

on BA and BE studies for orally

administered drug products. It does not

create or confer any rights for or on any

person and does not operate to bind

FDA or the public. An alternative

approach may be used if such an

approach satisfies the requirements of

the applicable statutes and regulations.

Interested persons may submit written

comments on the guidance to the

Dockets Management Branch (address

above). 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. The guidance and received

comments are available for public

examination in the Dockets

Management Branch between 9 a.m. and

4 p.m., Monday through Friday.

Dated: October 19, 2000.

Margaret M. Dotzel,

Associate Commissioner for Policy.

[FR Doc. 00–27602 Filed 10–26–00; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HOUSING AND

URBAN DEVELOPMENT

[Docket No. FR–4561–N–67]

Notice of Submission of Proposed

Information Collection to OMB;

Uniform Physical Standards and

Physical Inspection Requirements for

Certain HUD Housing, Administrative

Process for Assessment of Insured

and Assisted Properties

AGENCY: Office of the Chief Information

Officer, HUD.

ACTION: Notice.

SUMMARY: The proposed information

collection requirement described below

has been submitted to the Office of

Management and Budget (OMB) for

review, as required by the Paperwork

Reduction Act. The Department is

soliciting public comments on the

subject proposal.

DATES: Comments Due Date: November

27, 2000.

ADDRESSES: Interested persons are

invited to submit comments regarding

this proposal. Comments should refer to

the proposal by name and/or OMB

approval number (2502–0369) and

should be sent to: Joseph F. Lackey, Jr.,

OMB Desk Officer, Office of

Management and Budget, Room 10235,

New Executive Office Building,

Washington, DC 20503.

FOR FURTHER INFORMATION CONTACT:

Wayne Eddins, Reports Management

Officer, Q, Department of Housing and

Urban Development, 451 Seventh Street,

Southwest, Washington, DC 20410; email Wayne_Eddins@HUD.gov;

telephone (202) 708–2374. This is not a

toll-free number. Copies of the proposed

forms and other available documents

submitted to OMB may be obtained

from Mr. Eddins.

SUPPLEMENTARY INFORMATION: The

Department has submitted the proposal

for the collection of information, as

described below, to OMB for review, as

required by the Paperwork Reduction

Act (44 U.S.C. Chapter 35). The Notice

lists the following information: (1) The

title of the information collection

proposal; (2) the office of the agency to

collect the information; (3) the OMB

approval number, if applicable; (4) the

description of the need for the

information and its proposed use; (5)

the agency form number, if applicable;

(6) what members of the public will be

affected by the proposal; (7) how

frequently information submissions will

be required; (8) an estimate of the total

number of hours needed to prepare the

information submission including

number of respondents, frequency of

response, and hours of response; (9)

whether the proposal is new, an

extension, reinstatement, or revision of

an information collection requirement;

and (10) the name and telephone

number of an agency official familiar

with the proposal and of the OMB Desk

Officer for the Department.

This Notice also lists the following

information:

Title of Proposal: Uniform Physical

Standards and Physical Inspection

Requirements for Certain HUD Housing,

Administrative Process for Assessment

of Insured and Assisted Properties.

OMB Approval Number: 2502–0369.

Form Numbers: None.

Description of the Need for the

Information and its Proposed Use: The

uniform physical condition standards

are intended to ensure that HUD

program participants carry out their

legal obligations to maintain HUD

properties in a condition that is decent,

safe, sanitary, and in good repairs.

Respondents: Business or Other ForProfit.

Frequency of Submission: Annually.

Reporting Burden:

Number of

respondents × Frequency of response × Hours perresponse = Burden hours

7,100 1 9 153,900