[Federal Register Volume 65, Number 209 (Friday, October 27, 2000)]
[Notices]
[Pages 64449-64450]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-27602]



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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.

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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:  Mei-Ling 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-by-formulation 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 trade-off); 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 within-subject variability in the 
BA measures when compared to the reference product; (3) suggest whether 
a subject-by-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 (Sec. 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

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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]
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