Preliminary Draft Guidance for Industry on In Vivo Bioequivalence Studies Based on Population and Individual Bioequivalence Approaches; Availability

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availability of a preliminary draft guidance for industry entitled ``In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 If this preliminary draft guidance becomes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ADDRESSES: Copies of this preliminary draft guidance are available on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requests for single copies of the preliminary draft guidance for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Submit written comments on the preliminary draft guidance to the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preliminary draft guidance for industry entitled ``In Vivo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

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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]

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