67880 Federal Register / Vol. 62, No. 249 / Tuesday, December 30, 1997 / Notices

physically or chemically interact with a

drug substance. Altered BA of drug

products can lead to dosage adjustments

or, more commonly, to the provision of

specific dosing instructions in relation

to administration with meals. This draft

guidance provides a general design for

and recommends ways this information

can be appropriately addressed in the

labeling.

The draft guidance recommends that

a food-effect assessment should be made

early in drug development. It also

recommends that subsequent studies

following formulation changes may be

eliminated provided that there is basis

for assuming that the food-effect arises

due to drug substance rather than

formulation factors.

This draft guidance addresses

situations when food-effect BA and BE

studies should be considered and when

these may not be important. It examines

study considerations, such as general

design, subject selection, formulation

selection, test meal, treatment

administration, sample collection, and

data analysis. It also addresses issues

related to labeling for food effects.

This draft guidance document

represents the agency’s current thinking

on food-effect bioavailability and

bioequivalence studies. 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 approach

satisfies the requirements of the

applicable statute, regulations, or both.

Interested persons may submit written

comments on the draft guidance

document 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 The draft guidance and

received comments may be seen in the

office above between 9 a.m. and 4 p.m.,

Monday through Friday.

An electronic version of this guidance

is available on the World Wide Web at

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

index.htm.

Dated: December 18, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–33802 Filed 12-29-97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 97D–0433]

Preliminary Draft Guidance for

Industry on In Vivo Bioequivalence

Studies Based on Population and

Individual Bioequivalence Approaches;

Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is announcing the

availability of a preliminary draft

guidance for industry entitled ‘‘In Vivo

Bioequivalence Studies Based on

Population and Individual

Bioequivalence Approaches.’’ If this

preliminary draft guidance becomes

final, it will provide recommendations

to sponsors of investigational new drug

applications (IND’s), new drug

applications (NDA’s), abbreviated new

drug applications (ANDA’s), and

abbreviated antibiotic drug applications

(AADA’s) who intend to perform studies

based on a comparison of

pharmacokinetic metrics. If finalized,

the guidance would replace a prior

guidance entitled ‘‘Statistical

Procedures for Bioequivalence Studies

Using a Standard Two-Treatment

Crossover Design,’’ which was

published in July 1992. Because a

transition to the approaches delineated

in this document will require careful

consideration, FDA is making it

available as a preliminary draft.

DATES: Written comments may be

submitted on the preliminary draft

guidance document by March 2, 1998.

General comments on agency guidance

documents are welcome at any time.

ADDRESSES: Copies of this preliminary

draft guidance are available on the

Internet at ‘‘http://www.fda.gov/cder/

guidance/index.htm.’’ Written requests

for single copies of the preliminary draft

guidance for industry should be

submitted 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

preliminary draft guidance to the

Dockets Management Branch (HFD–

305), Food and Drug Administration,

12420 Parklawn Dr., rm 1–23, Rockville,

MD 20857.

FOR FURTHER INFORMATION CONTACT:

Mei-Ling Chen, Office of Clinical

Pharmacology and

Biopharmaceutics, Center for Drug

Evaluation and Research (HFD–

870), Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, 301–827–

5919, or

Rabindra N. Patnaik, Office of Generic

Drugs, Center for Drug Evaluation

and Research (HFD–651), 7500

Standish Pl., Food and Drug

Administration, Rockville, MD

20855, 301–827–5847.

SUPPLEMENTARY INFORMATION: FDA is

announcing the availability of a

preliminary draft guidance for industry

entitled ‘‘In Vivo Bioequivalence

Studies Based on Population and

Individual Bioequivalence

Approaches.’’ If it becomes final, this

guidance for industry will provide

recommendations to sponsors of IND’s,

NDA’s, ANDA’s, and AADA’s who

intend to perform in vivo

bioequivalence studies based on a

comparison of pharmacokinetic metrics,

either prior to or following approval.

The definitions of ‘‘bioavailability’’

and ‘‘bioequivalence;’’ the requirements

for submitting such data in NDA’s,

ANDA’s, and supplements; and the

types of in vivo studies that are

acceptable to establish bioavailability

and bioequivalence are set forth in 21

CFR part 320. These regulatory

definitions and requirements reflect

requirements in the Federal Food, Drug,

and Cosmetic Act and other agency

regulations.

Bioavailability and bioequivalence are

usually measured by in vivo studies

assessing metrics of a plasma or blood

concentration-time curve to establish

the rate and extent of absorption of an

appropriate active drug/metabolite

(bioavailability), or to compare the rate

and extent of absorption of a test and

reference formulation (bioequivalence).

In the July 1992 guidance for industry

entitled ‘‘Statistical Procedures for

Bioequivalence Studies Using a

Standard Two-Treatment Crossover

Design,’’ FDA recommended that a

standard in vivo bioequivalence study

design be based on administration of the

test and reference products on separate

occasions to healthy subjects, either in

single or multiple doses, with random

assignment to the two possible

sequences of drug product

administration.

Based on work performed during the

last several years by scientists within

and outside FDA, this preliminary draft

guidance for industry recommends that

the approach for determining average

bioequivalence discussed in the 1992
Federal Register / Vol. 62, No. 249 / Tuesday, December 30, 1997 / Notices 67881

guidance be replaced by two new

statistical approaches termed

‘‘population’’ and ‘‘individual’’

bioequivalence.

In contrast to the standard

bioequivalence approach, which focuses

on assessing and comparing only

population averages for a bioavailability

metric of interest for a test and reference

product, the population and individual

bioequivalence approaches assess and

compare both population averages and

population variances for the metric.

This preliminary draft guidance

recommends that the population

bioequivalence approach be used by

NDA sponsors who wish to assess

bioequivalence during the

investigational phase of drug

development. The preliminary draft

guidance recommends that the

individual bioequivalence approach be

used by sponsors of ANDA’s and

AADA’s to assess bioequivalence

between a generic and reference listed

drug, or by sponsors of NDA’s, ANDA’s,

and AADA’s who, during the

postapproval period, wish to reassess in

vivo bioequivalence when a change of

sufficient magnitude occurs in the

formulation and/or manufacturing of the

drug product. If finalized, this guidance

would replace the 1992 guidance.

Because transition to the approaches

delineated in this preliminary draft will

require careful consideration, FDA is

publishing it as a preliminary draft

guidance. The agency hopes to engage

the public in a discussion of the

justification for and implications of the

recommendations that are presented.

This public discussion may include a

number of activities, such as holding a

public workshop, creating an expert

panel, and other discussions and

deliberations as appropriate. At the

conclusion of this public discussion,

which is expected to take at least several

months, FDA may release the draft

document for a second round of public

comment. Despite the possibility that

the draft guidance may be released again

for comment, the public is encouraged

to comment now on this preliminary

version and, specifically, to provide

information that supports or refutes the

importance of its proposals.

Given the need for careful

consideration of some of the

recommendations in the preliminary

draft, FDA does not recommend

implementation of any of its provisions

at this time.

This preliminary draft guidance for

industry represents the agency’s current

thinking on in vivo bioequivalence

studies based on population and

individual bioequivalence approaches.

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 approach satisfies the

requirements of the applicable statute,

regulations, or both.

Interested persons may, at any time,

submit written comments on the

preliminary draft 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. A copy of the preliminary

draft guidance and received comments

may be seen in the office above between

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

Friday.

Dated: December 17, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–33795 Filed 12–29–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Health Care Financing Administration

[Document Identifier: HCFA–667]

Agency Information Collection

Activities: Proposed Collection;

Comment Request

AGENCY: Health Care Financing

Administration, HHS.

In compliance with the requirement

of section 3506(c)(2)(A) of the

Paperwork Reduction Act of 1995, the

Health Care Financing Administration

(HCFA), Department of Health and

Human Services, is publishing the

following summary of proposed

collections for public comment.

Interested persons are invited to send

comments regarding this burden

estimate or any other aspect of this

collection of information, including any

of the following subjects: (1) The

necessity and utility of the proposed

information collection for the proper

performance of the agency’s functions;

(2) the accuracy of the estimated

burden; (3) ways to enhance the quality,

utility, and clarity of the information to

be collected; and (4) the use of

automated collection techniques or

other forms of information technology to

minimize the information collection

burden.

Type of Information Collection

Request: Extension of a currently

approved collection; Title of

Information Collection: Alternate

Quality Assessment Survey; Form No.:

HCFA–667 (OMB# 0938–0650); Use:

The HCFA–667 is used in lieu of an

onsite survey for those Clinical

Laboratories Improvement Amendment

(CLIA) laboratories with good

performance as determined by their last

onsite survey. This form is designed to

determine current CLIA compliance as

well as prepare laboratories for future

onsite surveys. This system rewards

good performance and facilitates quality

assurance. Frequency: On occasion;

Affected Public: Business or other forprofit, Not-for-profit institutions,

Federal Government, State, Local or

Tribal Government; Number of

Respondents: 4,000; Total Annual

Responses: 4,000; Total Annual Hours:

10,000.

To obtain copies of the supporting

statement and any related forms for the

proposed paperwork collections

referenced above, access HCFA’s Web

Site address at http://www.hcfa.gov/

regs/prdact95.htm, or E-mail your

request, including your address, phone

number, OMB number, and HCFA

document identifier, to

Paperwork@hcfa.gov, or call the Reports

Clearance Office on (410) 786–1326.

Written comments and

recommendations for the proposed

information collections must be mailed

within 60 days of this notice directly to

the HCFA Paperwork Clearance Officer

designated at the following address:

HCFA, Office of Information Services,

Information Technology Investment

Management Group, Division of HCFA

Enterprise Standards Attention: Louis

Blank, Room C2–26–17, 7500 Security

Boulevard Baltimore, Maryland 21244–

1850.

Dated: December 18, 1997.

John P. Burke III,

HCFA Reports Clearance Officer, Office of

Information Services Information Technology

Investment Management Group Division of

HCFA Enterprise Standards.

[FR Doc. 97–33819 Filed 12–29–97; 8:45 am]

BILLING CODE 4120–03–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Health Care Financing Administration

[HCFA–1034–N]

Medicare Program; Request for

Nominations for Members for the

Practicing Physicians Advisory

Council

AGENCY: Health Care Financing

Administration (HCFA), HHS.

ACTION: Notice.