[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Draft Guidance for Industry on BA and BE Studies for Orally 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availability of a draft guidance for industry entitled ``BA and BE 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 This draft guidance provides recommendations to 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 This draft guidance 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DATES: Written comments on the draft guidance document may be submitted 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the draft guidance that are intended to reduce regulatory burden.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ADDRESSES: Copies of this draft guidance are available on the Internet 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single copies of the draft guidance to the Drug Information Branch 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 Submit written comments on the draft guidance to the Dockets 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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