[Federal Register Volume 62, Number 249 (Tuesday, December 30, 1997)]
[Notices]
[Pages 67880-67881]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-33795]



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Preliminary Draft Guidance for Industry on In Vivo Bioequivalence 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.

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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availability of a preliminary draft guidance for industry entitled ``In 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 If this preliminary draft guidance becomes 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DATES: Written comments may be submitted on the preliminary draft 
guidance document by March 2, 1998.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ADDRESSES: Copies of this preliminary draft guidance are available on 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requests for single copies of the preliminary draft guidance for 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Submit written comments on the preliminary draft guidance to the 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

[[Page 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