[Federal Register Volume 64, Number 171 (Friday, September 3, 1999)]
[Notices]
[Pages 48409-48410]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-23009]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 99D-2729]
Draft Guidance for Industry on BA and BE Studies for Orally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availability of a draft guidance for industry entitled ``BA and BE
Studies for Orally Administered Drug Products--General
Considerations.'' This draft guidance provides recommendations to
sponsors and applicants intending to submit bioavailability (BA) and/or
bioequivalence (BE) information in investigational new drug
applications (IND's), new drug applications (NDA's), abbreviated new
drug applications (ANDA's), and their amendments and supplements, to
the Center for Drug Evaluation and Research (CDER). This draft guidance
provides general information on how to comply with the BA and BE
requirements for orally administered dosage forms in 21 CFR part 320.
It is one of a set of planned core guidances designed to reduce and/or
eliminate the need for FDA drug-specific BA/BE guidances.
DATES: Written comments on the draft guidance document may be submitted
by November 2, 1999. Interested parties are invited to submit
information specifically to support or refute some of the approaches in
the draft guidance that are intended to reduce regulatory burden.
General comments on agency guidance documents are welcome at any time.
ADDRESSES: Copies of this draft guidance are available on the Internet
at ``http://www.fda.gov/cder/guidance/index.htm''. Submit written
requests for
[[Page 48410]]
single copies of the draft guidance to the Drug Information Branch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 Submit written comments on the draft guidance to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Vinod P. Shah, Center for Drug
Evaluation and Research (HFD-350), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-5635.
SUPPLEMENTARY INFORMATION: FDA is announcing the availability of a
draft guidance for industry entitled ``BA and BE Studies for Orally
Administered Drug Products--General Considerations.'' This draft
guidance provides recommendations to sponsors and applicants intending
to provide BA and BE information in IND's, NDA's, ANDA's, and their
amendments and supplements that complies with the BA and BE
requirements in 21 CFR part 320 as they apply to dosage forms intended
for oral administration.
This draft guidance focuses primarily on product quality BA and BE.
Product quality BA encompasses information related to release of the
drug substance from the drug product into systemic circulation. BE is a
formal comparative test that uses: (1) Specified criteria for
comparisons, (2) BE limits (goal posts), and (3) confidence intervals
to determine if the observed interval falls within the specified limit.
Many aspects of this draft guidance represent departures from past
practices used to document BE. Although some aspects of this draft
guidance may result in small increases of regulatory burden, the main
intent of many of these changes is to reduce the regulatory burden
while maintaining sound scientific principles consistent with public
health objectives. Specific examples of reduction of the regulatory
burden include: (1) Enable biowaivers for lower strengths of modified
release dosage forms, (2) eliminate multiple dose BE studies for
modified release dosage forms, (3) enable biowaivers for higher
strength of immediate release dosage forms, and (4) reduce emphasis on
measuring metabolites in BE studies. Respondents to the Federal
Register notice are encouraged to provide data that can be used to
support or refute proposals in the draft guidance.
In the past, BE studies have been performed as single-dose,
crossover studies in healthy volunteers. To compare measures in these
studies, data have been analyzed using an average BE criterion. In this
draft guidance, FDA recommends the use of new criteria to allow
comparison of BE. One, termed an individual BE criterion, means having
study designs in which both the test and reference drug products are
administered to the same individuals on two separate occasions
(replicate study designs). Another, termed a population BE criterion,
does not involve replicate study designs. The individual BE is
recommended for use in in vivo BE studies submitted in: (1) ANDA's, and
(2) NDA's and ANDA's when the need to redocument BE arises after
approval. The population BE criterion is recommended for use by
sponsors who conduct certain important in vivo BE studies (e.g.,
studies that compare clinical trial material with the to-be-marketed
dose form). The use of the proposed individual BE criterion is based on
the assessment of both means and variances of BA measures, to include a
subject-by-formulation (S*F) interaction variance and within-subject
variance for both test and reference products. Both population and
individual criteria allow scaling of the BE limit according to
variability of the reference product.
FDA has expended substantial effort in determining whether S*F
interaction and increased within-subject variability occur with
sufficient frequency to affect a conclusion of switchability between
test and reference products. FDA believes that additional information
on the frequency and the magnitude of the different variance terms, as
well as other information, is needed. For this reason, this draft
guidance is recommending that sponsors conduct all in vivo BE studies
for: (1) IND's, (2) NDA's, (3) ANDA's, and (4) amendments and
supplements to NDA's and ANDA's using replicate designs for a 2-year
period following the publication of the final version of this guidance.
For example, the current average BE criteria generally require 24
subjects in a two-period study design (total of 24 x 2 = 48 dosage
administrations). The proposed replicate study design would require 12
subjects in a four-period study (total of 12 x 2 x 2 dosage
administrations). However, there is no increase in total number of
dosage administrations to be analyzed. Sponsors can analyze their data
using either average or population criteria (IND's and NDA's) or
average or individual criteria (ANDA's and supplements to NDA's and
ANDA's). Sponsors should specify their choice in the study protocol
submitted to the appropriate institutional review board prior to study
initiation. At the sponsor's discretion, scaling may be used, under
certain circumstances, to judge BE when either an individual or
population criterion is specified. Because data from the recommended
replicate studies may be powered for an average BE criterion, the
burden of performing replicate BE studies is minimized. The agency in
turn will perform individual BE analyses on all submitted data to
determine subject x formulation interactions. Information from these
studies will enable FDA to assess further the usefulness of the
proposed individual and population BE criteria.
This draft guidance document is being issued consistent with FDA's
good guidance practices (62 FR 8961, February 27, 1997). It represents
the agency's current thinking on bioavailability and bioequivalence
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 statute, regulations, or
both.
Interested persons may submit written comments on the 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. The draft 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: August 25, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-23009 Filed 9-2-99; 8:45 am]
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